636 results on '"Bluestone JA"'
Search Results
2. Polyclonal Regulatory T Cell Therapy for Control of Inflammation in Kidney Transplants
- Author
-
Chandran, S, Tang, Q, Sarwal, M, Laszik, ZG, Putnam, AL, Lee, K, Leung, J, Nguyen, V, Sigdel, T, Tavares, EC, Yang, JYC, Hellerstein, M, Fitch, M, Bluestone, JA, and Vincenti, F
- Subjects
Organ Transplantation ,Clinical Research ,Kidney Disease ,Clinical Trials and Supportive Activities ,Transplantation ,Prevention ,Evaluation of treatments and therapeutic interventions ,Development of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,5.2 Cellular and gene therapies ,Renal and urogenital ,Adolescent ,Adult ,Aged ,Female ,Follow-Up Studies ,Glomerular Filtration Rate ,Graft Rejection ,Graft Survival ,Humans ,Inflammation ,Isoantigens ,Kidney Failure ,Chronic ,Kidney Function Tests ,Kidney Transplantation ,Male ,Middle Aged ,Pilot Projects ,Postoperative Complications ,Prognosis ,Risk Factors ,T-Lymphocytes ,Regulatory ,Tissue Donors ,Young Adult ,cellular biology ,clinical trial ,immune regulation ,immunobiology ,immunosuppressant - polyclonal preparations ,kidney transplantation/nephrology ,protocol biopsy ,rejection: subclinical ,translational research/science ,Medical and Health Sciences ,Surgery - Abstract
Early subclinical inflammation in kidney transplants is associated with later graft fibrosis and dysfunction. Regulatory T cells (Tregs) can reverse established inflammation in animal models. We conducted a pilot safety and feasibility trial of autologous Treg cell therapy in three kidney transplant recipients with subclinical inflammation noted on 6-month surveillance biopsies. Tregs were purified from peripheral blood and polyclonally expanded ex vivo using medium containing deuterated glucose to label the cells. All patients received a single infusion of ~320 × 106 (319, 321, and 363.8 × 106 ) expanded Tregs. Persistence of the infused Tregs was tracked. Graft inflammation was monitored with follow-up biopsies and urinary biomarkers. Nearly 1 × 109 (0.932, 0.956, 1.565 × 109 ) Tregs were successfully manufactured for each patient. There were no infusion reactions or serious therapy-related adverse events. The infused cells demonstrated patterns of persistence and stability similar to those observed in non-immunosuppressed subjects receiving the same dose of Tregs. Isolation and expansion of Tregs is feasible in kidney transplant patients on immunosuppression. Infusion of these cells was safe and well tolerated. Future trials will test the efficacy of polyclonal and donor alloantigen-reactive Tregs for the treatment of inflammation in kidney transplants.
- Published
- 2017
3. InterleuKin-33 And Interferon-Γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation During Immune Perturbation
- Author
-
Molofsky, AB, Van Gool, F, Liang, HE, Van Dyken, SJ, Nussbaum, JC, Lee, J, Bluestone, JA, and Locksley, RM
- Subjects
Immunology - Abstract
Group 2 innate lymphoid cells (ILC2s) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis in adipose tissue and contribute to tissue repair during injury. Here we show that interleukin-33 (IL-33) mediates activation of ILC2s and Treg cells in resting adipose tissue, but also after helminth infection or treatment with IL-2. Unexpectedly, ILC2-intrinsic IL-33 activation was required for Treg cell accumulation invivo and was independent of ILC2 type 2 cytokines but partially dependent on direct co-stimulatory interactions via ICOSL-ICOS. IFN-γ inhibited ILC2 activation and Treg cell accumulation by IL-33 in infected tissue, as well as adipose tissue, where repression increased with aging and high-fat diet-induced obesity. IL-33 and ILC2s are central mediators of type 2 immune responses that promote tissue and metabolic homeostasis, and IFN-γ suppresses this pathway, likely to promote inflammatory responses and divert metabolic resources necessary to protect the host.
- Published
- 2015
4. Tolerance induction and reversal of diabetes in mice transplanted with human embryonic stem cell-derived pancreatic endoderm
- Author
-
Szot, GL, Yadav, M, Lang, J, Kroon, E, Kerr, J, Kadoya, K, Brandon, EP, Baetge, EE, Bour-Jordan, H, and Bluestone, JA
- Subjects
Developmental Biology ,Biological Sciences ,Medical and Health Sciences - Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells in the islets of Langerhans. In most cases, reversal of disease would require strategies combining islet cell replacement with immunotherapy that are currently available only for the most severely affected patients. Here, we demonstrate that immunotherapies that target T cell costimulatory pathways block the rejection of xenogeneic human embryonic-stem-cell-derived pancreatic endoderm (hESC-PE) in mice. The therapy allowed for long-term development of hESC-PE into islet-like structures capable of producing human insulin and maintaining normoglycemia. Moreover, short-term costimulation blockade led to robust immune tolerance that could be transferred independently of regulatory T cells. Importantly, costimulation blockade prevented the rejection of allogeneic hESC-PE by human PBMCs in a humanized model in vivo. These results support the clinical development of hESC-derived therapy, combined with tolerogenic treatments, as a sustainable alternative strategy for patients with T1D.
- Published
- 2015
5. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: Metabolic and immunologic features at baseline identify a subgroup of responders
- Author
-
Herold, KC, Gitelman, SE, Ehlers, MR, Gottlieb, PA, Greenbaum, CJ, Hagopian, W, Boyle, KD, Keyes-Elstein, L, Aggarwal, S, Phippard, D, Sayre, PH, McNamara, J, and Bluestone, JA
- Subjects
Endocrinology & Metabolism ,Clinical Sciences ,Medical Physiology - Published
- 2014
6. Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: A randomized controlled trial
- Author
-
Herold, KC, Gitelman, SE, Willi, SM, Gottlieb, PA, Waldron-Lynch, F, Devine, L, Sherr, J, Rosenthal, SM, Adi, S, Jalaludin, MY, Michels, AW, Dziura, J, and Bluestone, JA
- Subjects
Endocrinology & Metabolism ,Clinical Sciences ,Medical Physiology - Published
- 2014
7. Corrigendum to 'Mechanisms of PDL1-mediated regulation of autoimmune diabetes' [Clin. Immunol. 125 (2007) 16-25]
- Author
-
Guleria, I, Bupp, MG, Dada, S, Fife, BT, Tang, Q, Ansari, MJ, Trikudanathan, S, Vadivel, N, Fiorina, P, Yagita, H, Azuma, M, Atkinson, M, Bluestone, JA, and Sayegh, MH
- Subjects
Immunology - Published
- 2014
8. Clinical Grade Manufacturing of Human Alloantigen-Reactive Regulatory T Cells for Use in Transplantation
- Author
-
Putnam, AL, Safinia, N, Medvec, A, Laszkowska, M, Wray, M, Mintz, MA, Trotta, E, Szot, GL, Liu, W, Lares, A, Lee, K, Laing, A, Lechler, RI, Riley, JL, Bluestone, JA, Lombardi, G, and Tang, Q
- Subjects
Organ Transplantation ,Transplantation ,Biotechnology ,Prevention ,5.2 Cellular and gene therapies ,Development of treatments and therapeutic interventions ,Animals ,Cell- and Tissue-Based Therapy ,Flow Cytometry ,Graft Rejection ,Graft vs Host Disease ,Humans ,Immune Tolerance ,Isoantigens ,Lymphocyte Activation ,Mice ,Mice ,Inbred BALB C ,Skin Transplantation ,T-Lymphocytes ,Regulatory ,Transplantation Tolerance ,Cellular therapy ,clinical application ,regulatory T cells ,tolerance induction ,Medical and Health Sciences ,Surgery - Abstract
Regulatory T cell (Treg) therapy has the potential to induce transplantation tolerance so that immunosuppression and associated morbidity can be minimized. Alloantigen-reactive Tregs (arTregs) are more effective at preventing graft rejection than polyclonally expanded Tregs (PolyTregs) in murine models. We have developed a manufacturing process to expand human arTregs in short-term cultures using good manufacturing practice-compliant reagents. This process uses CD40L-activated allogeneic B cells to selectively expand arTregs followed by polyclonal restimulation to increase yield. Tregs expanded 100- to 1600-fold were highly alloantigen reactive and expressed the phenotype of stable Tregs. The alloantigen-expanded Tregs had a diverse TCR repertoire. They were more potent than PolyTregs in vitro and more effective at controlling allograft injuries in vivo in a humanized mouse model.
- Published
- 2013
9. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs β-cell function
- Author
-
Long, SA, Rieck, M, Sanda, S, Bollyky, JB, Samuels, PL, Goland, R, Ahmann, A, Rabinovitch, A, Aggarwal, S, Phippard, D, Turka, LA, Ehlers, MR, Bianchine, PJ, Boyle, KD, Adah, SA, Bluestone, JA, Buckner, JH, and Greenbaum, CJ
- Subjects
Endocrinology & Metabolism ,Clinical Sciences ,Medical Physiology - Published
- 2013
10. Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial
- Author
-
Herold, KC, Gitelman, SE, Willi, SM, Gottlieb, PA, Waldron-Lynch, F, Devine, L, Sherr, J, Rosenthal, SM, Adi, S, Jalaludin, MY, Michels, AW, Dziura, J, and Bluestone, JA
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Trials and Supportive Activities ,Autoimmune Disease ,Diabetes ,Clinical Research ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Metabolic and endocrine ,Adolescent ,Antibodies ,Monoclonal ,Humanized ,C-Peptide ,Diabetes Mellitus ,Type 1 ,Female ,Glycated Hemoglobin ,Humans ,Insulin ,Male ,Autoimmunity ,Immune therapy ,Type 1 diabetes ,Paediatrics and Reproductive Medicine ,Public Health and Health Services ,Endocrinology & Metabolism ,Clinical sciences ,Public health - Abstract
Aims/hypothesisType 1 diabetes results from a chronic autoimmune process continuing for years after presentation. We tested whether treatment with teplizumab (a Fc receptor non-binding anti-CD3 monoclonal antibody), after the new-onset period, affects the decline in C-peptide production in individuals with type 1 diabetes.MethodsIn a randomised placebo-controlled trial we treated 58 participants with type 1 diabetes for 4-12 months with teplizumab or placebo at four academic centres in the USA. A central randomisation centre used computer generated tables to allocate treatments. Investigators, patients, and caregivers were blinded to group assignment. The primary outcome was a comparison of C-peptide responses to a mixed meal after 1 year. We explored modification of treatment effects in subgroups of patients.ResultsThirty-four and 29 subjects were randomized to the drug and placebo treated groups, respectively. Thirty-one and 27, respectively, were analysed. Although the primary outcome analysis showed a 21.7% higher C-peptide response in the teplizumab-treated group (0.45 vs 0.371; difference, 0.059 [95% CI 0.006, 0.115] nmol/l) (p = 0.03), when corrected for baseline imbalances in HbA(1c) levels, the C-peptide levels in the teplizumab-treated group were 17.7% higher (0.44 vs 0.378; difference, 0.049 [95% CI 0, 0.108] nmol/l, p = 0.09). A greater proportion of placebo-treated participants lost detectable C-peptide responses at 12 months (p = 0.03). The teplizumab group required less exogenous insulin (p
- Published
- 2013
11. Erratum
- Author
-
Atkinson, MA, Bluestone, JA, Eisenbarth, GS, Hebrok, M, Herold, KC, Accili, D, Pietropaolo, M, Arvan, PR, Von Herrath, M, Markel, DS, and Rhodes, CJ
- Subjects
Medical and Health Sciences ,Endocrinology & Metabolism - Published
- 2012
12. How does type 1 diabetes develop? The notion of homicide or β-cell suicide revisited (Diabetes (2011) 60, (1370-1379))
- Author
-
Atkinson, MA, Bluestone, JA, Eisenbarth, GS, Hebrok, M, Herold, KC, Accili, D, Pietropaolo, M, Arvan, PR, Von Herrath, M, Markel, DS, and Rhodes, CJ
- Subjects
Endocrinology & Metabolism ,Medical and Health Sciences - Published
- 2012
13. MicroRNA 10a marks regulatory T cells
- Author
-
Bluestone, Jeffrey, Jeker, LT, Zhou, X, Gershberg, K, de, D, Morar, MM, Stadthagen, G, Lund, AH, and Bluestone, JA
- Abstract
MicroRNAs (miRNAs) are crucial for regulatory T cell (Treg) stability and function. We report that microRNA-10a (miR-10a) is expressed in Tregs but not in other T cells including individual thymocyte subsets. Expression profiling in inbred mouse strains de
- Published
- 2012
14. In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation.
- Author
-
Earle, KE, Tang, Q, Zhou, X, Liu, W, Zhu, S, Bonyhadi, ML, and Bluestone, JA
- Subjects
CD4-Positive T-Lymphocytes ,Humans ,Autoimmune Diseases ,L-Selectin ,Receptors ,Chemokine ,Receptors ,Interleukin-2 ,Repressor Proteins ,Interleukin-2 ,HLA-DR Antigens ,Immunotherapy ,Flow Cytometry ,Cell Culture Techniques ,Immunomagnetic Separation ,Immunophenotyping ,Lymphocyte Activation ,Forkhead Transcription Factors ,Receptors ,CCR6 ,regulatory T cells ,autoimmunity ,Treg ,CD4+CD25+ ,suppression ,human ,Receptors ,Chemokine ,CCR6 ,Immunology - Abstract
Regulatory T cells (Tregs) have been shown to be critical in the balance between autoimmunity and tolerance and have been implicated in several human autoimmune diseases. However, the small number of Tregs in peripheral blood limits their therapeutic potential. Therefore, we developed a protocol that would allow for the expansion of Tregs while retaining their suppressive activity. We isolated CD4+CD25 hi cells from human peripheral blood and expanded them in vitro in the presence of anti-CD3 and anti-CD28 magnetic Xcyte Dynabeads and high concentrations of exogenous Interleukin (IL)-2. Tregs were effectively expanded up to 200-fold while maintaining surface expression of CD25 and other markers of Tregs: CD62L, HLA-DR, CCR6, and FOXP3. The expanded Tregs suppressed proliferation and cytokine secretion of responder PBMCs in co-cultures stimulated with anti-CD3 or alloantigen. Treg expansion is a critical first step before consideration of Tregs as a therapeutic intervention in patients with autoimmune or graft-versus-host disease.
- Published
- 2005
15. RIBP, a novel Rlk/Txk- and itk-binding adaptor protein that regulates T cell activation.
- Author
-
Rajagopal, K, Sommers, CL, Decker, DC, Mitchell, EO, Korthauer, U, Sperling, AI, Kozak, CA, Love, PE, and Bluestone, JA
- Subjects
Killer Cells ,Natural ,T-Lymphocytes ,Cells ,Cultured ,Cell Line ,Tumor Cells ,Cultured ,Animals ,Mice ,Inbred Strains ,Mice ,Knockout ,Humans ,Muridae ,Mice ,Lymphoma ,T-Cell ,Adaptor Proteins ,Signal Transducing ,Carrier Proteins ,Recombinant Proteins ,Interleukin-2 ,Chromosome Mapping ,Cloning ,Molecular ,Crosses ,Genetic ,Transfection ,Sequence Alignment ,Lymphocyte Activation ,Amino Acid Sequence ,Sequence Homology ,Amino Acid ,Gene Library ,Molecular Sequence Data ,Protein-Tyrosine Kinases ,T cell activation ,signal transduction ,adaptor protein ,Tec tyrosine kinases ,T helper type 1/T helper type 2 cells ,Adaptor Proteins ,Signal Transducing ,Cells ,Cultured ,Cloning ,Molecular ,Crosses ,Genetic ,Killer Cells ,Natural ,Lymphoma ,T-Cell ,Inbred Strains ,Knockout ,Sequence Homology ,Amino Acid ,Tumor Cells ,Medical and Health Sciences ,Immunology - Abstract
A novel T cell-specific adaptor protein, RIBP, was identified based on its ability to bind Rlk/Txk in a yeast two-hybrid screen of a mouse T cell lymphoma library. RIBP was also found to interact with a related member of the Tec family of tyrosine kinases, Itk. Expression of RIBP is restricted to T and natural killer cells and is upregulated substantially after T cell activation. RIBP-disrupted knockout mice displayed apparently normal T cell development. However, proliferation of RIBP-deficient T cells in response to T cell receptor (TCR)-mediated activation was significantly impaired. Furthermore, these activated T cells were defective in the production of interleukin (IL)-2 and interferon gamma, but not IL-4. These data suggest that RIBP plays an important role in TCR-mediated signal transduction pathways and that its binding to Itk and Rlk/Txk may regulate T cell differentiation.
- Published
- 1999
16. Dissociation of intracellular signaling pathways in response to partial agonist ligands of the T cell receptor.
- Author
-
Chau, LA, Bluestone, JA, and Madrenas, J
- Subjects
T-Lymphocytes ,Clone Cells ,Animals ,Mice ,Receptors ,Antigen ,T-Cell ,Ligands ,Signal Transduction ,Phosphorylation ,ZAP-70 Protein-Tyrosine Kinase ,Protein-Tyrosine Kinases ,CD4 Antigens ,T cell receptor ,partial agonist ,signal transduction ,mitogen-activated protein kinases ,p120-GAP ,Medical and Health Sciences ,Immunology - Abstract
The T cell receptor (TCR) is a versatile receptor able to generate different signals that result in distinct T cell responses. The pattern of early signals is determined by the TCR binding kinetics that control the ability of the ligand to coengage TCR and coreceptor. Coengagement of TCR and CD4 results in an agonist signaling pattern with complete tyrosine phosphorylation of TCR subunits, and recruitment and activation of ZAP-70. In contrast, TCR engagement without CD4 coengagement causes a partial agonist type of signaling, characterized by distinct phosphorylation of TCR subunits and recruitment but no activation of ZAP-70. The pathways triggered by partial agonist signaling are unknown. Here, we show that agonists cause association of active lck and active ZAP-70 with p120-GTPase-activating protein (p120-GAP). These associations follow engagement of CD4 or CD3, respectively. In contrast, partial agonists do not activate lck or ZAP-70, but induce association of p120-GAP with inactive ZAP-70. Despite these differences, both agonist and partial agonist signals activate the mitogen-activated protein kinase (MAPK) pathway. However, MAPK activation by partial agonists is transient, supporting a kinetic, CD4-dependent model for the mechanism of action of variant TCR ligands. Transient MAPK activation may explain some of the responses to TCR partial agonists and antagonists.
- Published
- 1998
17. T cell receptor-gamma/delta cells protect mice from herpes simplex virus type 1-induced lethal encephalitis.
- Author
-
Sciammas, R, Kodukula, P, Tang, Q, Hendricks, RL, and Bluestone, JA
- Subjects
Trigeminal Ganglion ,T-Lymphocytes ,Animals ,Mice ,Inbred BALB C ,Mice ,Inbred C57BL ,Mice ,Simplexvirus ,Encephalitis ,Viral ,Herpes Simplex ,Keratitis ,Herpetic ,Receptors ,Antigen ,T-Cell ,gamma-delta ,Immunohistochemistry ,Virus Replication ,Interferon-gamma ,Neurodegenerative ,Brain Disorders ,Infectious Diseases ,Sexually Transmitted Infections ,Emerging Infectious Diseases ,2.1 Biological and endogenous factors ,2.2 Factors relating to the physical environment ,Infection ,Inflammatory and immune system ,Medical and Health Sciences ,Immunology - Abstract
Increased numbers of T cell receptor (TCR)-gamma/delta cells have been observed in animal models of influenza and sendai virus infections, as well as in patients infected with human immunodeficiency virus and herpes simplex virus type 1 (HSV-1). However, a direct role for TCR-gamma/delta cells in protective immunity for pathogenic viral infection has not been demonstrated. To define the role of TCR-gamma/delta cells in anti-HSV-1 immunity, TCR-alpha-/- mice treated with anti- TCR-gamma/delta monoclonal antibodies or TCR-gamma/delta x TCR-alpha/beta double-deficient mice were infected with HSV-1 by footpad or ocular routes of infection. In both models of HSV-1 infection, TCR-gamma/delta cells limited severe HSV-1-induced epithelial lesions and greatly reduced mortality by preventing the development of lethal viral encephalitis. The observed protection resulted from TCR-gamma/delta cell-mediated arrest of both viral replication and neurovirulence. The demonstration that TCR-gamma/delta cells play an important protective role in murine HSV-1 infections supports their potential contribution to the immune responses in human HSV-1 infection. Thus, this study demonstrates that TCR-gamma/delta cells may play an important regulatory role in human HSV-1 infections.
- Published
- 1997
18. Nonmitogenic anti-CD3 monoclonal antibodies deliver a partial T cell receptor signal and induce clonal anergy.
- Author
-
Smith, JA, Tso, JY, Clark, MR, Cole, MS, and Bluestone, JA
- Subjects
Lymph Nodes ,T-Lymphocytes ,Animals ,Mice ,Inbred BALB C ,Mice ,Inbred DBA ,Mice ,Phosphotyrosine ,Receptors ,Antigen ,T-Cell ,Antibodies ,Monoclonal ,Immunosuppression ,Lymphocyte Activation ,Signal Transduction ,Receptor Aggregation ,Clonal Anergy ,Phosphorylation ,ZAP-70 Protein-Tyrosine Kinase ,Protein-Tyrosine Kinases ,CD3 Complex ,Antibodies ,Monoclonal ,Inbred BALB C ,Inbred DBA ,Receptors ,Antigen ,T-Cell ,Medical and Health Sciences ,Immunology - Abstract
Anti-CD3 monoclonal antibodies (mAbs) are potent immunosuppressive agents used in clinical transplantation. However, the activation-related adverse side effects associated with these mAbs have prompted the development of less toxic nonmitogenic anti-CD3 mAb therapies. At present, the functional and biochemical consequences of T cell exposure to nonmitogenic anti-CD3 is unclear. In this study, we have examined the early signaling events triggered by a nonmitogenic anti-CD3 mAb. Like the mitogenic anti-CD3 mAb, nonnmitogenic anti-CD3 triggered changes in the T cell receptor (TCR) complex, including zeta chain tyrosine phosphorylation and ZAP-70 association. However, unlike the mitogenic anti-CD3 stimulation, nonmitogenic anti-CD3 was ineffective at inducing the highly phosphorylated form of zeta (p23) and tyrosine phosphorylation of the associated ZAP-70 tyrosine kinase. This proximal signaling deficiency correlated with minimal phospholipase Cgamma-1 phosphorylation and failure to mobilize detectable Ca2+. Not only did biochemical signals delivered by nonmitogenic anti-CD3 resemble altered peptide ligand signaling, but exposure of Th1 clones to nonmitogenic anti-CD3 also resulted in functional anergy. Finally, a bispecific anti-CD3 X anti-CD4 F(ab)'2 reconstituted early signal transduction events and induced proliferation, suggesting that defective association of lck with the TCR complex may underlie the observed signaling differences between the mitogenic and nonmitogenic anti-CD3.
- Published
- 1997
19. The efficiency of CD4 recruitment to ligand-engaged TCR controls the agonist/partial agonist properties of peptide-MHC molecule ligands.
- Author
-
Madrenas, J, Chau, LA, Smith, J, Bluestone, JA, and Germain, RN
- Subjects
Th1 Cells ,Cell Line ,Animals ,Mice ,Peptides ,Receptors ,Antigen ,T-Cell ,Signal Transduction ,Major Histocompatibility Complex ,Amino Acid Sequence ,Phosphorylation ,Molecular Sequence Data ,Receptors ,Antigen ,T-Cell ,Medical and Health Sciences ,Immunology - Abstract
One hypothesis seeking to explain the signaling and biological properties of T cell receptor for antigen (TCR) partial agonists and antagonists is the coreceptor density/kinetic model, which proposes that the pharmacologic behavior of a TCR ligand is largely determined by the relative rates of (a) dissociation ofligand from an engaged TCR and (b) recruitment oflck-linked coreceptors to this ligand-engaged receptor. Using several approaches to prevent or reduce the association of CD4 with occupied TCR, we demonstrate that consistent with this hypothesis, the biological and biochemical consequence of limiting this interaction is to convert typical agonists into partial agonist stimuli. Thus, adding anti-CD4 antibody to T cells recognizing a wild-type peptide-MHC class II ligand leads to disproportionate inhibition of interleukin-2 (IL-2) relative to IL-3 production, the same pattern seen using a TCR partial agonist/antagonist. In addition, T cells exposed to wild-type ligand in the presence of anti-CD4 antibodies show a pattern of TCR signaling resembling that seen using partial agonists, with predominant accumulation of the p21 tyrosine-phosphorylated form of TCR-zeta, reduced tyrosine phosphorylation of CD3epsilon, and no detectable phosphorylation of ZAP-70. Similar results are obtained when the wild-type ligand is presented by mutant class II MHC molecules unable to bind CD4. Likewise, antibody coligation of CD3 and CD4 results in an agonist-like phosphorylation pattern, whereas bivalent engagement of CD3 alone gives a partial agonist-like pattern. Finally, in accord with data showing that partial agonists often induce T cell anergy, CD4 blockade during antigen exposure renders cloned T cells unable to produce IL-2 upon restimulation. These results demonstrate that the biochemical and functional responses to variant TCR ligands with partial agonist properties can be largely reproduced by inhibiting recruitment of CD4 to a TCR binding a wild-type ligand, consistent with the idea that the relative rates of TCR-ligand disengagement and of association of engaged TCR with CD4 may play a key role in determining the pharmacologic properties of peptide-MHC molecule ligands. Beyond this insight into signaling through the TCR, these results have implications for models of thymocyte selection and the use of anti-coreceptor antibodies in vivo for the establishment ofimmunological tolerance.
- Published
- 1997
20. CTLA-4: a negative regulator of autoimmune disease.
- Author
-
Karandikar, NJ, Vanderlugt, CL, Walunas, TL, Miller, SD, and Bluestone, JA
- Subjects
Neurodegenerative ,Neurosciences ,Autoimmune Disease ,Multiple Sclerosis ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Abatacept ,Amino Acid Sequence ,Animals ,Antigens ,CD ,Antigens ,Differentiation ,Autoantigens ,CTLA-4 Antigen ,Encephalomyelitis ,Autoimmune ,Experimental ,Female ,Immunization ,Passive ,Immunoconjugates ,Interferon-gamma ,Interleukin-2 ,Lymphocyte Activation ,Mice ,Mice ,Inbred Strains ,Molecular Sequence Data ,Myelin Basic Protein ,Peptides ,Medical and Health Sciences ,Immunology - Abstract
CTLA-4, a CD28 homologue expressed on activated T cells, binds with high affinity to the CD28 ligands, B7-1 (CD80) and B7-2 (CD86). This study was designed to examine the role of CTLA-4 in regulating autoimmune disease. Murine relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) is a demyelinating disease mediated by PLP139-151-specific CD4+ T cells in SJL/J mice. Anti-CTLA-4 mAbs (or their F(ab) fragments) enhanced in vitro proliferation and pro-inflammatory cytokine production by PLP139-151-primed lymph node cells. Addition of either reagent to in vitro activation cultures potentiated the ability of T cells to adoptively transfer disease to naive recipients. In vivo administration of anti-CTLA-4 mAb to recipients of PLP139-151-specific T cells resulted in accelerated and exacerbated disease. Finally, anti-CTLA-4 treatment of mice during disease remission resulted in the exacerbation of relapses. Collectively, these results suggest that CTLA-4 mediates the downregulation of ongoing immune responses and plays a major role in regulating autoimmunity.
- Published
- 1996
21. Immune deviation of 2C transgenic intraepithelial lymphocytes in antigen-bearing hosts.
- Author
-
Guehler, SR, Bluestone, JA, and Barrett, TA
- Subjects
Biotechnology ,Emerging Infectious Diseases ,Vaccine Related ,Biodefense ,Prevention ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Animals ,Cytokines ,Dose-Response Relationship ,Immunologic ,Female ,H-2 Antigens ,Immune Tolerance ,Immunity ,Mucosal ,Immunophenotyping ,Interleukin-2 ,Interleukin-4 ,Intestinal Mucosa ,Ketoglutarate Dehydrogenase Complex ,Lymph Nodes ,Lymphocyte Activation ,Male ,Mice ,Mice ,Inbred BALB C ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Receptors ,Antigen ,T-Cell ,alpha-beta ,T-Lymphocyte Subsets ,Medical and Health Sciences ,Immunology - Abstract
The present study examined self-tolerance for T cell receptor (TCR) alpha beta intestinal intraepithelial lymphocytes (iIELs) using the 2C transgenic (Tg) mouse model specific for a peptide antigen (Ag) presented by the class I major histocompatibility complex H-2Ld. Although Tg+ T cells were largely deleted from the periphery of Ag+ mice, equivalent numbers of Tg iIELs were present in Ag+ compared to Ag- mice. Tg iIELs in Ag- mice contained CD8 alpha beta, CD8 alpha alpha, and CD4-CD8- subsets, whereas only CD8 alpha alpha and CD4-CD8- Tg iIEL subsets were detected in Ag+ mice. Analysis of surface markers revealed that Tg iIELs in Ag+ mice expressed decreased levels of Thy-1 and increased CD45R/B220 as compared to Ag- Tg iIELs. In response to activation with exogenous peptide or immobilized anti-TCR mAB, iIELs from Ag- mice proliferated at high levels and produced interleukin (IL)-2 and interferon (IFN)-gamma, while Tg+ iIELs from Ag+ mice proliferated at low levels and failed to produce detectable IL-2 or IFN-gamma. Activation of sorted iIEL subsets from Ag- mice revealed that CD8 alpha alpha and CD4-CD8- subsets produced low levels of IL-2 and IFN-gamma in response to activation with antigen-presenting cells and added peptide or immobilized anti-TCR mAb, while CD8 alpha beta + iIELs responded to endogenous levels of peptide. In response to APC and exogenous peptide, sorted iIEL subsets from Ag+ mice produced IL-2 and IFN-gamma, and proliferated at greatly reduced levels compared to corresponding subsets from Ag- mice. Analysis of cytokine mRNA levels revealed that activation in vitro induced IL-2 mRNA only in Ag-, but not Ag+ iIELs, whereas a high level of IL-4 mRNA induction was detected in Tg+ iIELs from Ag+ mice, and to a lesser degree, from Ag- mice. These data suggest that tolerance for Tg+ iIELs resulted in the deletion of CD8 alpha beta + subsets and the persistence of Tg+ iIEL subsets with decreased sensitivity to endogenous levels of self-peptide. A comparison of the cytokine profiles expressed by Tg+ iIEL subsets in Ag- and Ag+ mice suggested that tolerance induction had involved the functional deviation of cells from TC1 (T helper-1-like) to a less inflammatory TC2 (T helper-2-like) phenotype capable of mediating humoral immune responses in the mucosa.
- Published
- 1996
22. CTLA-4 ligation blocks CD28-dependent T cell activation.
- Author
-
Walunas, TL, Bakker, CY, and Bluestone, JA
- Subjects
Abatacept ,Animals ,Antibodies ,Monoclonal ,Antigens ,CD ,Antigens ,Differentiation ,CD28 Antigens ,CTLA-4 Antigen ,Cell Cycle ,Cell Line ,Cell Survival ,Cells ,Cultured ,Cricetinae ,Cytokines ,Immunoconjugates ,Interleukin-2 ,Kinetics ,Lymphocyte Activation ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Receptors ,Antigen ,T-Cell ,T-Lymphocytes ,Medical and Health Sciences ,Immunology - Abstract
CTLA-4 is a CD28 homologue believed to be a negative regulator of T cell function. However, the mechanism of this downregulatory activity is not well understood. The present study was designed to examine the effect of CTLA-4 ligation on cytokine production, cell survival, and cell cycle progression. The results demonstrate that the primary effect of CTLA-4 ligation is not the induction of apoptosis. Instead, CTLA-4 signaling blocks IL-2 production, IL-2 receptor expression, and cell cycle progression of activated T cells. Moreover, the effect of CTLA-4 signaling was manifested after initial T cell activation. Inhibition of IL-2 receptor expression and cell cycle progression was more pronounced at late (72 h) time points after initial activation. The effects of anti-CTLA-4 mAbs were most apparent in the presence of optimal CD28-mediated costimulation consistent with the finding that CTLA-4 upregulation was CD28-dependent. Finally, the addition of exogenous IL-2 to the cultures restored IL-2 receptor expression and T cell proliferation. These results suggest that CTLA-4 signaling does not regulate cell survival or responsiveness to IL-2, but does inhibit CD28-dependent IL-2 production.
- Published
- 1996
23. CD43 is a murine T cell costimulatory receptor that functions independently of CD28.
- Author
-
Sperling, AI, Green, JM, Mosley, RL, Smith, PL, DiPaolo, RJ, Klein, JR, Bluestone, JA, and Thompson, CB
- Subjects
Immunization ,Vaccine Related ,Biotechnology ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Aetiology ,Underpinning research ,Inflammatory and immune system ,Animals ,Antibodies ,Monoclonal ,Antigens ,CD ,CD28 Antigens ,CD3 Complex ,Leukosialin ,Ligands ,Lymph Nodes ,Lymphocyte Activation ,Mice ,Mice ,Inbred BALB C ,Mice ,Inbred C57BL ,Mice ,Mutant Strains ,Sialoglycoproteins ,Signal Transduction ,Specific Pathogen-Free Organisms ,T-Lymphocyte Subsets ,Thymus Gland ,Medical and Health Sciences ,Immunology - Abstract
Costimulation mediated by the CD28 receptor has been shown to play an important role in the development of a vigorous T cell immune response. Nevertheless, CD28-deficient mice can mount effective T cell-dependent immune responses. These data suggest that other costimulatory molecules may play a role in T cell activation. In a search for other costimulatory receptors on T cells, we have characterized a monoclonal antibody (mAb) that can costimulate T cells in the absence of accessory cells. Similar to CD28 antibodies, this mAb, R2/60, was found to synergize with T cell receptor engagement in inducing proliferation. Independent ligation of CD3 and the ligand recognized by R2/60 results in T cell proliferation, suggesting that the two molecules do not have to colocalize to activate the R2/60 costimulatory pathway. R2/60 does not react with CD28, and furthermore, R2/60 costimulates in a CD28-independent fashion since the mAb costimulates T cells from the CD28-deficient mice as well as wild-type mice. Expression cloning of the R2/60 antigen identified the ligand as murine CD43. Together, these data demonstrate that CD43 can serve as a receptor on T cells that can provide CD28-independent costimulation.
- Published
- 1995
24. Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse.
- Author
-
Lenschow, DJ, Ho, SC, Sattar, H, Rhee, L, Gray, G, Nabavi, N, Herold, KC, and Bluestone, JA
- Subjects
Diabetes ,Autoimmune Disease ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Abatacept ,Animals ,Antibodies ,Monoclonal ,Antigens ,CD ,Antigens ,Differentiation ,Antigens ,Differentiation ,T-Lymphocyte ,B7-1 Antigen ,B7-2 Antigen ,CTLA-4 Antigen ,Diabetes Mellitus ,Type 1 ,Female ,Immunoconjugates ,Lectins ,C-Type ,Lymphocyte Activation ,Male ,Membrane Glycoproteins ,Mice ,Mice ,Inbred C57BL ,Mice ,Inbred NOD ,T-Lymphocytes ,Medical and Health Sciences ,Immunology - Abstract
Insulin-dependent diabetes mellitus (IDDM) is thought to be an immunologically mediated disease resulting in the complete destruction of the insulin-producing islets of Langerhans. It has become increasingly clear that autoreactive T cells play a major role in the development and progression of this disease. In this study, we examined the role of the CD28/B7 costimulation pathway in the development and progression of autoimmune diabetes in the nonobese diabetic (NOD) mouse model. Female NOD mice treated at the onset of insulitis (2-4 wk of age) with CTLA4Ig immunoglobulin (Ig) (a soluble CD28 antagonist) or a monoclonal antibody (mAb) specific for B7-2 (a CD28 ligand) did not develop diabetes. However, neither of these treatments altered the disease process when administered late, at > 10 wk of age. Histological examination of islets from the various treatment groups showed that while CTLA4Ig and anti-B7-2 mAb treatment blocked the development of diabetes, these reagents had little effect on the development or severity of insulitis. Together these results suggest that blockade of costimulatory signals by CTLA4Ig or anti-B7-2 acts early in disease development, after insulitis but before the onset of frank diabetes. NOD mice were also treated with mAbs to another CD28 ligand, B7-1. In contrast to the previous results, the anti-B7-1 treatment significantly accelerated the development of disease in female mice and, most interestingly, induced diabetes in normally resistant male mice. A combination of anti-B7-1 and anti-B7-2 mAbs also resulted in an accelerated onset of diabetes, similar to that observed with anti-B7-1 mAb treatment alone, suggesting that anti-B7-1 mAb's effect was dominant. Furthermore, treatment with anti-B7-1 mAbs resulted in a more rapid and severe infiltrate. Finally, T cells isolated from the pancreas of these anti-B7-1-treated animals exhibited a more activated phenotype than T cells isolated from any of the other treatment groups. These studies demonstrate that costimulatory signals play an important role in the autoimmune process, and that different members of the B7 family have distinct regulatory functions during the development of autoimmune diabetes.
- Published
- 1995
25. Phenotypic and functional analysis of positive selection in the gamma/delta T cell lineage.
- Author
-
Wells, FB, Tatsumi, Y, Bluestone, JA, Hedrick, SM, Allison, JP, and Matis, LA
- Subjects
HIV/AIDS ,Neurodegenerative ,Autoimmune Disease ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Animals ,Cell Differentiation ,Cyclosporine ,Mice ,Mice ,Inbred BALB C ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Phenotype ,Receptors ,Antigen ,T-Cell ,gamma-delta ,Signal Transduction ,T-Lymphocytes ,Thymus Gland ,Medical and Health Sciences ,Immunology - Abstract
Recent evidence suggests that T cells expressing gamma/delta antigen receptors (T cell receptor [TCR]) are subject to positive selection during development. We have shown that T cells expressing a class I major histocompatibility complex (MHC)-specific gamma/delta TCR transgene (tg) are not positively selected in class I MHC-deficient, beta 2-microglobulin (beta 2m) gene knockout mice (tg+ beta 2m-). In this report, we examine phenotypic and functional parameters of gamma/delta positive selection in this transgenic model system. TCR-gamma/delta tg+ thymocytes of mature surface phenotype (heat stable antigen-, CD5hi) were found in beta 2m+ but not in beta 2m- mice. Moreover, subsets of tg+ thymocytes with the phenotype of activated T cells (interleukin [IL]2R+, CD44hi, or Mel-14lo) were also present only in the beta 2m+ mice. Cyclosporine A, which blocks positive selection of TCR-alpha/beta T cells, also inhibited gamma/delta tg+ T cell development. These results support the idea that positive selection of TCR-gamma/delta requires active TCR-mediated signal transduction. Whereas tg+ beta 2m+ thymocytes produced IL-2 and proliferated when stimulated by alloantigen, TCR engagement of tg+ beta 2m- thymocytes by antigen induced IL-2R expression but was uncoupled from the signal transduction pathway leading to IL-2 production and autocrine proliferation. Overall, these results demonstrate significant parallels between gamma/delta and alpha/beta lineage development, and suggest a general role for TCR signaling in thymic maturation.
- Published
- 1993
26. Peptide-induced conformational changes in class I heavy chains alter major histocompatibility complex recognition.
- Author
-
Bluestone, JA, Jameson, S, Miller, S, and Dick, R
- Subjects
Inflammatory and immune system ,Amino Acid Sequence ,Animals ,Antibodies ,Monoclonal ,Binding Sites ,Cell Transformation ,Viral ,Histocompatibility Antigens Class I ,Humans ,Lymphoma ,Major Histocompatibility Complex ,Molecular Sequence Data ,Mutagenesis ,Site-Directed ,Ovalbumin ,Peptides ,Protein Conformation ,Rauscher Virus ,Tumor Cells ,Cultured ,Medical and Health Sciences ,Immunology - Abstract
Small peptides, derived from endogenous proteins bind within the antigen binding groove created by the beta-pleated sheets and alpha helices of the alpha 1 and alpha 2 domains of the class I molecule of the major histocompatibility complex (MHC). However, the precise role of peptide in class I MHC conformation remains unclear. Here, we have shown that, in at least some instances, changes induced in the MHC molecule by the binding of distinct peptides can be identified as specific alterations in serological epitopes expressed on the class I protein. The nature of specific peptides expressed by class I-bearing cells may, therefore, have a dramatic influence on T cell development, self-tolerance, and alloreactivity.
- Published
- 1992
27. Immunoregulatory functions for murine intraepithelial lymphocytes: gamma/delta T cell receptor-positive (TCR+) T cells abrogate oral tolerance, while alpha/beta TCR+ T cells provide B cell help.
- Author
-
Fujihashi, K, Taguchi, T, Aicher, WK, McGhee, JR, Bluestone, JA, Eldridge, JH, and Kiyono, H
- Subjects
Emerging Infectious Diseases ,Vaccine Related ,Aetiology ,Underpinning research ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Animals ,Antibody Formation ,Antigens ,Surface ,B-Lymphocytes ,Cell Adhesion ,Digestive System ,Epithelial Cells ,Interleukin-5 ,Intestinal Mucosa ,Lectins ,Lymphocytes ,Mice ,Mice ,Inbred C3H ,Phenotype ,Plant Lectins ,Receptors ,Antigen ,T-Cell ,alpha-beta ,Receptors ,Antigen ,T-Cell ,gamma-delta ,T-Lymphocyte Subsets ,T-Lymphocytes ,T-Lymphocytes ,Helper-Inducer ,Medical and Health Sciences ,Immunology - Abstract
Past work has shown that a subset of effector T cells with unique characteristics could abrogate hapten- or antigen-induced tolerance, and the reconstitution of this immune response has been termed contrasuppression. We have studied contrasuppression in a model of oral tolerance (OT) in which adoptively transferred antigen-specific T contrasuppressor (Tcs) cells reverse OT and result in antibody responses to the eliciting antigen. In the present study, we show that murine intraepithelial lymphocytes (IELs) from mice orally immunized with sheep red blood cells (SRBC) contain T cells that exhibit Tcs cell activity. This effect was mediated by CD3+ gamma/delta T cell receptor-positive (TCR+), but not alpha/beta TCR+ T cells, and gamma/delta TCR+ Tcs cells were associated with both the CD4-,CD8+ and CD4-,CD8- (double-negative) IEL fractions. The CD4-,CD8+ gamma/delta TCR+ IELs were further separated into Vicia villosa-adherent and -nonadherent fractions. Adoptive transfer of V. villosa-adherent gamma/delta TCR+ T cells to mice with OT to SRBC resulted in splenic IgA, IgM, and IgG subclass anti-SRBC responses, while V. villosa-nonadherent gamma/delta TCR+ T cells were without activity. The gamma/delta TCR+ IELs did not support in vitro antibody responses in B cell cultures, while alpha/beta TCR+ IELs were effective T helper cells. Further, cytokine production by the gamma/delta TCR+ IELs was examined, and the gamma/delta TCR+ V. villosa-adherent fraction, which possessed contrasuppressor function, contained low levels of IL-5 mRNA and small numbers of IL-5-producing cells when compared with alpha/beta TCR+ IELs and V. villosa-nonadherent gamma/delta TCR+ IELs. Our results now show that mouse IELs contain two distinct types of T cells that function in the immune response, e.g., alpha/beta TCR+ T cells that produce IL-5 and function as helper cells, and gamma/delta TCR+ T cells that restore antibody responses in mice that had been orally tolerized with antigen.
- Published
- 1992
28. A protective role of gamma/delta T cells in primary infection with Listeria monocytogenes in mice.
- Author
-
Hiromatsu, K, Yoshikai, Y, Matsuzaki, G, Ohga, S, Muramori, K, Matsumoto, K, Bluestone, JA, and Nomoto, K
- Subjects
Biodefense ,Infectious Diseases ,Emerging Infectious Diseases ,Foodborne Illness ,Prevention ,Vaccine Related ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Good Health and Well Being ,Animals ,Antibodies ,Monoclonal ,Antigens ,Differentiation ,T-Lymphocyte ,CD3 Complex ,CD4 Antigens ,CD8 Antigens ,Female ,Flow Cytometry ,Heat-Shock Proteins ,Listeria monocytogenes ,Listeriosis ,Lymph Nodes ,Mice ,Mice ,Inbred C3H ,Mycobacterium tuberculosis ,Receptors ,Antigen ,T-Cell ,Recombinant Proteins ,T-Lymphocyte Subsets ,T-Lymphocytes ,Medical and Health Sciences ,Immunology - Abstract
We have previously reported that T cells bearing T cell receptors (TCRs) of gamma/delta type appear at a relatively early stage of primary infection with Listeria monocytogenes in mice. To characterize the early-appearing gamma/delta T cells during listeriosis, we analyzed the specificity and cytokine production of the gamma/delta T cells in the peritoneal cavity in mice inoculated intraperitoneally with a sublethal dose of L. monocytogenes. The early-appearing gamma/delta T cells, most of which were of CD4-CD8- phenotype, proliferated and secreted IFN-gamma and macrophage chemotactic factor in response to purified protein derivative from Mycobacterium tuberculosis, or recombinant 65-kD heat-shock protein derived from M. bovis but not to heat-killed Listeria. To further elucidate the potential role of the gamma/delta T cells in the host-defense mechanism against primary infection with Listeria, we examined the effects of in vivo administration of monoclonal antibodies (mAbs) against TCR-gamma/delta or TCR-alpha/beta on the bacterial eradication in mice infected with Listeria. Most of alpha/beta T cells or gamma/delta T cells were depleted in the peripheral lymphoid organs at least for 12 d after an intraperitoneal injection of 200 micrograms TCR-alpha/beta mAb or 200 micrograms TCR-gamma/delta mAb, respectively. An exaggerated bacterial multiplication was evident at the early stage of listerial infection in the gamma/delta T cells-depleted mice, whereas the alpha/beta T cell-depleted mice exhibited much the same resistance level as the control mice at this stage although the resistance was severely impaired at the late stage after listerial infection.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1992
29. Adoptive Regulatory T Cell Therapy in a Patient with Systemic Lupus Erythematosus
- Author
-
Dall'Era, M, Pauli, ML, Remedios, K, Taravati, K, Sandoval, PM, Putnam, AL, Lares, A, Haemel, A, Tang, Q, Hellerstein, M, Fitch, M, McNamara, J, Welch, B, Bluestone, JA, Wofsy, D, Rosenblum, MD, and Autoimmunity Centers of Excellence
- Subjects
hemic and immune systems ,chemical and pharmacologic phenomena ,Autoimmunity Centers of Excellence - Abstract
OBJECTIVE:Regulatory T cell (Treg) adoptive cell therapy has great potential to treat autoimmune disease. Currently, very little is known about how these cells impact inflamed tissues. The purpose of this study was to elucidate how autologous Treg therapy influences tissue inflammation in human autoimmune disease. METHODS:We describe a patient with systemic lupus erythematosus (SLE) with active skin disease that received adoptive Treg therapy. We comprehensively quantify Tregs and immune activation in peripheral blood and skin with time post-treatment. RESULTS:Deuterium tracking of infused Tregs revealed the transient presence of cells in peripheral blood accompanied by increased percentages of highly activated Tregs in diseased skin. Flow cytometric analysis and whole transcriptome RNA sequencing (RNAseq) revealed that Treg accumulation in skin was associated with a marked attenuation of the IFNγ pathway and a reciprocal augmentation of the IL-17 pathway. This phenomenon was more pronounced in skin relative to peripheral blood. To validate these findings, we found that Treg adoptive transfer in a murine model of skin inflammation also resulted in a pronounced skewing away from Th1 immunity and towards IL-17 production. CONCLUSIONS:We report the first case of a patient with SLE treated with autologous adoptive Treg therapy. Taken together, our results suggest that this treatment results in increased activated Tregs in inflamed skin with a dynamic shift from Th1 to Th17 responses. This article is protected by copyright. All rights reserved.
- Published
- 2018
30. Structure and specificity of T cell receptor gamma/delta on major histocompatibility complex antigen-specific CD3+, CD4-, CD8- T lymphocytes.
- Author
-
Bluestone, JA, Cron, RQ, Cotterman, M, Houlden, BA, and Matis, LA
- Subjects
Emerging Infectious Diseases ,Underpinning research ,Development of treatments and therapeutic interventions ,1.1 Normal biological development and functioning ,5.2 Cellular and gene therapies ,Inflammatory and immune system ,Amino Acid Sequence ,Animals ,Antigens ,Differentiation ,T-Lymphocyte ,Base Sequence ,Blotting ,Northern ,Blotting ,Southern ,CD3 Complex ,Cell Line ,Cytotoxicity ,Immunologic ,Gene Rearrangement ,gamma-Chain T-Cell Antigen Receptor ,Histocompatibility Antigens Class I ,Lymphocyte Activation ,Major Histocompatibility Complex ,Mice ,Mice ,Inbred Strains ,Molecular Sequence Data ,Molecular Weight ,Receptors ,Antigen ,T-Cell ,Receptors ,Antigen ,T-Cell ,gamma-delta ,T-Lymphocytes ,T-Lymphocytes ,Cytotoxic ,Medical and Health Sciences ,Immunology - Abstract
Analyses of TCR-bearing murine and human T cells have defined a unique subpopulation of T cells that express the TCR-gamma/delta proteins. The specificity of TCR-gamma/delta T cells and their role in the immune response have not yet been elucidated. Here we examine alloreactive TCR-gamma/delta T cell lines and clones that recognize MHC-encoded antigens. A BALB/c nu/nu (H-2d)-derived H-2k specific T cell line and derived clones were both cytolytic and released lymphokines after recognition of a non-classical H-2 antigen encoded in the TL region of the MHC. These cells expressed the V gamma 2/C gamma 1 protein in association with a TCR-delta gene product encoded by a Va gene segment rearranged to two D delta and one J delta variable elements. A second MHC-specific B10 nu/nu (H-2b) TCR-gamma/delta T cell line appeared to recognize a classical H-2D-encoded MHC molecule and expressed a distinct V gamma/C gamma 4-encoded protein. These data suggest that many TCR-gamma/delta-expressing T cells may recognize MHC-linked antigens encoded within distinct subregions of the MHC. The role of MHC-specific TCR-gamma/delta cells in immune responses and their immunological significance are discussed.
- Published
- 1988
31. Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance.
- Author
-
Ildstad, ST, Wren, SM, Bluestone, JA, Barbieri, SA, and Sachs, DH
- Subjects
Biotechnology ,Transplantation ,Inflammatory and immune system ,Animals ,Antibody-Producing Cells ,Bone Marrow Transplantation ,Chimera ,Cytotoxicity ,Immunologic ,Hemagglutination ,Immune Tolerance ,Immunocompetence ,In Vitro Techniques ,Lymphocyte Culture Test ,Mixed ,Male ,Mice ,Mice ,Inbred Strains ,Skin Transplantation ,Transplantation Immunology ,Transplantation ,Homologous ,Transplantation ,Isogeneic ,Medical and Health Sciences ,Immunology - Abstract
Mixed allogeneically reconstituted mice (B10 + B10.D2----B10) that specifically accept B10.D2 tail skin allografts were examined for in vivo and in vitro immunocompetence, patterns of hematopoietic repopulation, and in vitro reactivity. In vitro, mixed allogeneic chimeras (B10 + B10.D2----B10) manifested specific tolerance in mixed lymphocyte reactions and cell-mediated lympholysis to B10 and B10.D2 splenocytes, with normal responses to third-party (B10.BR) cells. Such chimeras were immunocompetent in B cell and helper T cell responses, as assessed by their primary plaque forming cell responses to in vivo sheep red blood cell immunization. This is in contrast to fully allogeneic chimeras, which responded less well. In addition, survival of the mixed allogeneic chimeras in a conventional animal facility was superior to that of fully allogeneic chimeras, and similar to syngeneically reconstituted (B10----B10) mice. Specific tolerance to skin grafts, degree of allogeneic engraftment, and persistence of chimerism was also assessed in a noncongenic mixed allogeneic combination (B10 + C3H----B10). Such animals manifested specific hyporeactivity to C3H skin allografts, but eventual chronic rejection of the grafts occurred in spite of stable and persistent mixed chimerism. MHC-congenic (B10.BR) skin grafts were accepted indefinitely in the same animals, suggesting that skin-specific non-major histocompatibility complex antigens were responsible for rejection of the C3H skin allografts.
- Published
- 1985
32. Evidence for a regulatory idiotypic network in the in vivo response to H-2 antigens.
- Author
-
Rabinowitz, R, Bluestone, JA, and Sachs, DH
- Subjects
Immunization ,Biotechnology ,Inflammatory and immune system ,Animals ,Antibodies ,Anti-Idiotypic ,B-Lymphocytes ,Graft Rejection ,H-2 Antigens ,Immunoglobulin Idiotypes ,Mice ,Mice ,Inbred BALB C ,Rabbits ,Rats ,Skin Transplantation ,Transplantation ,Homologous ,Medical and Health Sciences ,Immunology - Abstract
Treatment of BALB/c mice with purified pig antiidiotype to 11-4.1 (anti-H-2Kk) monoclonal antibody has been found previously to induce the appearance of idiotype-bearing molecules (Id') in the serum of these mice, in the absence of detectable antigen-binding activity. In the present study we examined the effect of subsequent immunization of such antiidiotype-primed mice with the original H-2Kk antigen. Skin grafting of virgin BALB/c mice with BALB.K skin did not generate any detectable Id' antibodies when tested by enzyme-linked immunosorbent assay (ELISA). In contrast, grafting of antiidiotype-primed mice with BALB.K skin specifically boosted ther serum level of Id' molecules. Challenge of antiidiotype-primed mice with either B10.D2 or rat skin had no effect on the production of such Id' molecules. Absorption studies demonstrated that the majority of Id' molecules induced by H-2Kk antigenic stimulus and detected in ELISA are antigen-nonbinding molecules, thus indicating specific restimulation by the original H-2Kk antigen of nonbinding idiotype-positive B cell clones. The relevance of these findings to the existence of network interactions in the immune response to H-2 antigens is discussed.
- Published
- 1985
33. Cloned cytotoxic T lymphocytes that recognize an I-A region product in the context of a class I antigen.
- Author
-
Shinohara, N, Bluestone, JA, and Sachs, DH
- Subjects
Animals ,Antibodies ,Monoclonal ,Clone Cells ,Female ,Genetic Complementation Test ,H-2 Antigens ,Histocompatibility Antigens Class II ,Male ,Mice ,Mutation ,T-Lymphocytes ,Cytotoxic ,Medical and Health Sciences ,Immunology - Abstract
Cloned CTLs QM3 and QM7 isolated from a bulk CTL line B10.QBR anti-B10.MBR recognized a combination of the H-2Kb molecule and an I-Ak subregion gene product. Such a combinatorial specificity was revealed by complementation of the target antigen in F1 animals between two negative parental strains carrying H-2Kb and I-Ak, respectively. We confirmed the involvement of the H-2Kb molecule by blocking killing with anti-Kb mAb and failure of certain mutant H-2Kb genes to complement with I-Ak to generate the determinant in F1 animals. Although the nature of the I-Ak subregion gene product is not definitive, there was a correlation between the expression of Ia antigens on the cell surface and susceptibility of the cells to lysis by these CTLs, suggesting that it is the classical I-Ak class II antigen.
- Published
- 1986
34. Production of a T cell hybridoma that expresses the T cell receptor gamma/delta heterodimer.
- Author
-
Yokoyama, WM, Koning, F, Stingl, G, Bluestone, JA, Coligan, JE, and Shevach, EM
- Subjects
Development of treatments and therapeutic interventions ,5.2 Cellular and gene therapies ,Animals ,Antigens ,Differentiation ,T-Lymphocyte ,Antigens ,Surface ,Cell Line ,Hybridomas ,Interleukin-2 ,Mice ,Receptors ,Antigen ,T-Cell ,T-Lymphocytes ,Medical and Health Sciences ,Immunology - Abstract
We have produced a T cell hybridoma line by fusion of an IL-2-dependent, long-term T cell receptor (TCR) gamma/delta+ Thy-1+, bone marrow-derived, dendritic epidermal cell line to the BW5147 tumor line. The resultant hybridoma was rapidly growing, lymphokine independent, and expressed T3 in association with the TCR gamma/delta heterodimer. Several subclones of the hybridoma line produced easily detectable levels of IL-2 after stimulation by anti-T3 or Con A. The availability of these cloned cell lines should greatly facilitate further functional, biochemical, and molecular studies of the TCR delta chain.
- Published
- 1987
35. Antiidiotypes against anti-H-2 monoclonal antibodies. V. In vivo antiidiotype treatment induces idiotype-specific helper T cells.
- Author
-
Auchincloss, H, Bluestone, JA, and Sachs, DH
- Subjects
Biotechnology ,Immunization ,Vaccine Related ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Animals ,Antibodies ,Anti-Idiotypic ,Antibodies ,Monoclonal ,B-Lymphocytes ,Binding Sites ,Antibody ,Immunization ,Passive ,Immunoglobulin Heavy Chains ,Immunoglobulin Idiotypes ,Immunoglobulin Variable Region ,Isoantibodies ,Mice ,Mice ,Inbred BALB C ,Mice ,Nude ,Rabbits ,Swine ,T-Lymphocytes ,Helper-Inducer ,Medical and Health Sciences ,Immunology - Abstract
Mice have been treated in vivo with xenogeneic antiidiotypes prepared against a murine monoclonal anti-H-2Kk antibody, 11-4.1. B cell immune responses have been found to be altered by such treatment as evidenced by a modification in the idiotypic repertoire of the humoral response to H-2 antigens. Transfer of purified T cells into nude mice before anti-idiotype treatment showed that T cells are involved in the induction of idiotope-bearing antibodies by xenogeneic antiidiotype. Studies using bone marrow chimeras indicate that the environment in which either T or B cells mature does not appear to alter VH region genetic control of induction of antiidiotype-induced molecules. By adoptive transfer studies, T cells from antiidiotype-treated mice were found capable of modifying the idiotypic repertoire of B cells subsequently exposed to antigen even when the T cells were obtained from antiidiotype-primed mice of inappropriate allotype. Although it still must be determined whether idiotypic or antiidiotypic T cells are involved in such B cell idiotype regulation, these results indicate that some T cell functions are altered by xenogeneic antiidiotypes prepared against B cell products and suggest that T cell immunity to major histocompatibility complex antigens may also be affected by such reagents.
- Published
- 1983
36. Idiotypes of anti-Ia antibodies. I. Expression of the 14-4-4S idiotype in humoral immune responses.
- Author
-
Epstein, SL, Ozato, K, Bluestone, JA, and Sachs, DH
- Subjects
Biotechnology ,Immunization ,Vaccine Related ,Inflammatory and immune system ,Animals ,Antibodies ,Antibodies ,Monoclonal ,Antibody Formation ,Antibody Specificity ,Histocompatibility Antigens Class II ,Immunoglobulin Idiotypes ,Mice ,Mice ,Inbred C3H ,Medical and Health Sciences ,Immunology - Abstract
The idiotype of a mouse monoclonal anti-I-E antibody, 14-4-4S, has been studied using a heterologous anti-idiotypic reagent. This antibody recognizes Ia. 7, an antigenic specificity present in all strains expressing a product of the I-E subregion. Expression of the 14-4-4S idiotype in humoral immune responses was analyzed by an idiotype-specific enzyme-linked immunosorbent assay system. The idiotype was readily detectable in C3H.SW anti-C3H alloantisera, the same immunization combination from which the hybridoma was derived. Absorption analysis demonstrated the anti-I-E specificity of the idiotype-positive molecules in these alloantisera. Penetrance of idiotype expression was high among individual C3H.SW immune mice (9 of 10 tested). To examine genetic requirements for idiotype expression, an immunization was performed using as responders CWB mice, congenic with C3H.SW but differing at the heavy chain allotype loci. Immune sera of individual CWB mice contained very little or no idiotype, demonstrating that levels of idiotype expression are influenced by allotype-linked genes, although the influence of other genes has not been ruled. The 14-4-4S idiotype therefore represents a shared idiotype of anti-Ia antibodies and provides opportunities for analysis of the idiotypes of cellular receptors for the corresponding Ia antigen.
- Published
- 1981
37. A single amino acid substitution in the alpha 3 domain of an H-2 class I molecule abrogates reactivity with CTL.
- Author
-
Potter, TA, Bluestone, JA, and Rajan, TV
- Subjects
Vaccine Related ,Genetics ,Amino Acids ,Animals ,Cell Line ,DNA ,H-2 Antigens ,Histocompatibility Antigen H-2D ,Interleukin-2 ,Mice ,Mutation ,Structure-Activity Relationship ,T-Lymphocytes ,Cytotoxic ,Transfection ,Medical and Health Sciences ,Immunology - Abstract
We previously described a somatic cell expressing a variant H-2Dd molecule that did not serve as a target for alloreactive anti-Dd CTL. The mutant cell line had been isolated by its failure to express a serological epitope present on the H-2Dd alpha 3 domain. In the present study the alpha 3 domain of the Dd molecule of this somatic cell variant was sequenced and a single nucleotide change resulting in a glutamic acid to lysine substitution at residue 227 was identified. This change was reproduced in the cloned H-2Dd gene by oligonucleotide-directed mutagenesis. Cells transfected with this mutant gene were not killed by anti-H-2Dd CTL. Because previous studies using hybrid H-2 class I molecules had established that the alpha 3 domain does not express allele-specific determinants recognized by CTL, our results raise the possibility that residues in the alpha 3 domain of H-2 class I molecules are critical for CTL recognition and constitute a conserved (or monomorphic) determinant recognized by CTL.
- Published
- 1987
38. Revealing the specificity of regulatory T cells in murine autoimmune diabetes (vol 115, pg 5265, 2018)
- Author
-
Spence, A, Purtha, W, Tam, J, Dong, S, Kim, Y, Ju, C-H, Sterling, T, Nakayama, M, Robinson, WH, Bluestone, JA, Anderson, MS, and Tang, Q
- Published
- 2018
39. Targeting ABL-IRE1 alpha Signaling Spares ER-Stressed Pancreatic beta Cells to Reverse Autoimmune Diabetes (vol 25, pg 883, 2017)
- Author
-
Morita, S, Villalta, SA, Feldman, HC, Register, AC, Rosenthal, W, Hoffmann-Petersen, IT, Mehdizadeh, M, Ghosh, R, Wang, L, Colon-Negron, K, Meza-Acevedo, R, Backes, BJ, Maly, DJ, Bluestone, JA, and Papa, FR
- Published
- 2017
40. Targeting ABL-IRE1 alpha Signaling Spares ER- Stressed Pancreatic beta Cells to Reverse Autoimmune Diabetes
- Author
-
Morita, S, Villalta, SA, Feldman, HC, Register, AC, Rosenthal, W, Hoffmann-Petersen, IT, Mehdizadeh, M, Ghosh, R, Wang, L, Colon-Negron, K, Meza-Acevedo, R, Backes, BJ, Maly, DJ, Bluestone, JA, and Papa, FR
- Published
- 2017
41. A step closer to effective transplant tolerance?
- Author
-
Turka, LA, Bluestone, JA, Waldmann, H, and Sykes, M
- Subjects
General Medicine ,General Biochemistry, Genetics and Molecular Biology - Published
- 2016
42. Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial
- Author
-
Gitelman, SE, Gottlieb, PA, Felner, EI, Willi, SM, Fisher, LK, Moran, A, Gottschalk, M, Moore, WV, Pinckney, A, Keyes-Elstein, L, Harris, KM, Kanaparthi, S, Phippard, D, Ding, L, Bluestone, JA, Ehlers, MR, and Team, ITNSTARTS
- Subjects
Type 1 diabetes ,Thymoglobulin ,Beta cells ,Tcells ,Tregs ,C-peptide ,START trial ,ATG - Published
- 2016
43. CD4+ group 1 innate lymphoid cells (ILC) form a functionally distinct ILC subset that is increased in systemic sclerosis (vol 196, pg 2051, 2016)
- Author
-
Roan, F, Stoklasek, TA, Whalen, E, Molitor, JA, Bluestone, JA, Buckner, JH, and Ziegler, SF
- Published
- 2016
44. CD4+ Group 1 Innate Lymphoid Cells (ILC) Form a Functionally Distinct ILC Subset That Is Increased in Systemic Sclerosis
- Author
-
Roan, F, Stoklasek, TA, Whalen, E, Molitor, JA, Bluestone, JA, Buckner, JH, and Ziegler, SF
- Subjects
CD4-Positive T-Lymphocytes ,Inflammatory and immune system ,Systemic ,Immunology ,Cell Separation ,Flow Cytometry ,Scleroderma ,body regions ,T-Lymphocyte Subsets ,2.1 Biological and endogenous factors ,Humans ,Aetiology ,skin and connective tissue diseases ,Oligonucleotide Array Sequence Analysis - Abstract
Innate lymphoid cells (ILC) are a heterogeneous group of cellular subsets that produce large amounts of T cell-associated cytokines in response to innate stimulation in the absence of Ag. In this study, we define distinct patterns of surface marker and cytokine expression among the ILC subsets that may further delineate their migration and function. Most notably, we found that the subset previously defined as group 1 ILC (ILC1) contains CD4(+) CD8(-), CD4(-) CD8(+), and CD4(-) CD8(-) populations. Although all ILC1 subsets shared characteristics with Th1 cells, CD4(+) ILC1 also demonstrated significant phenotypic and functional heterogeneity. We also show that the frequencies of CD4(+) ILC1 and NKp44(+) group 3 ILC, but not CD4(-) ILC1 or group 2 ILC, are increased in the peripheral blood of individuals with systemic sclerosis (SSc), a disease characterized by fibrotic and vascular pathology, as well as immune dysregulation. Furthermore, we demonstrate that CD4(+) and CD4(-) ILC1 are functionally divergent based on their IL-6Rα expression and that the frequency of IL-6Rα expression on ILC is altered in SSc. The distinct phenotypic and functional features of CD4(+) and CD4(-) ILC1 suggest that they may have differing roles in the pathogenesis of immune-mediated diseases, such as SSc.
- Published
- 2016
45. Control of PI(3) kinase in Tregcells maintains homeostasis and lineage stability
- Author
-
Huynh, A, Dupage, M, Priyadharshini, B, Sage, PT, Quiros, J, Borges, CM, Townamchai, N, Gerriets, VA, Rathmell, JC, Sharpe, AH, Bluestone, JA, and Turka, LA
- Abstract
© 2015 Nature America, Inc. Foxp3+regulatory T cells (Tregcells) are required for immunological homeostasis. One notable distinction between conventional T cells (T conv cells) and Tregcells is differences in the activity of phosphatidylinositol-3-OH kinase (PI(3)K); only T conv cells downregulate PTEN, the main negative regulator of PI(3)K, upon activation. Here we found that control of PI(3)K in Tregcells was essential for lineage homeostasis and stability. Mice lacking Pten in Tregcells developed an autoimmune-lymphoproliferative disease characterized by excessive T helper type 1 (TH1) responses and B cell activation. Diminished control of PI(3)K activity in Tregcells led to reduced expression of the interleukin-2 (IL-2) receptor α subunit CD25, accumulation of Foxp3+CD2+cells and, ultimately, loss of expression of the transcription factor Foxp3 in these cells. Collectively, our data demonstrate that control of PI(3)K signaling by PTEN in Tregcells is critical for maintaining their homeostasis, function and stability.
- Published
- 2015
46. Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy
- Author
-
Van Gool, F, Molofsky, AB, Morar, MM, Rosenzwajg, M, Liang, HE, Klatzmann, D, Locksley, RM, and Bluestone, JA
- Subjects
Inflammatory and immune system ,Clinical Sciences ,Immunology ,Immunity ,Cardiorespiratory Medicine and Haematology ,Autoimmune Disease ,Antibodies ,Paediatrics and Reproductive Medicine ,Mice ,Eosinophilia ,Animals ,Humans ,Interleukin-2 ,Innate ,2.1 Biological and endogenous factors ,Lymphocytes ,Interleukin-5 ,Aetiology ,Cell Proliferation - Abstract
© 2014 by The American Society of Hematology. Interleukin (IL)-2 promotes regulatory T-cell development and function, and treatment with IL-2 is being tested as therapy for some autoimmune diseases. However, patients receiving IL-2 treatment also experience eosinophilia due to an unknown mechanism. Here, we show that patients receiving low-dose IL-2 have elevated levels of serum IL-5, and this correlates with their degree of eosinophilia. In mice, low-dose IL-2-anti-IL-2 antibody complexes drove group 2 innate lymphoid cells (ILC2) to produce IL-5 and proliferate. Using genetic approaches in mice, we demonstrate that activation of ILC2 was responsible for the eosinophilia observed with IL-2 therapy. These observations reveal anovel cellular network that is activated during IL-2 treatment. A better understanding of the cross talk between these cell populations may lead to more effective targeting of IL-2 to treat autoimmune disease.
- Published
- 2014
47. Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation
- Author
-
Molofsky, AB, VanGool, F, Liang, HE, VanDyken, SJ, Nussbaum, JC, Lee, J, Bluestone, JA, and Locksley, RM
- Abstract
© 2015 Elsevier Inc. Group 2 innate lymphoid cells (ILC2s) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis in adipose tissue and contribute to tissue repair during injury. Here we show that interleukin-33 (IL-33) mediates activation of ILC2s and Treg cells in resting adipose tissue, but also after helminth infection or treatment with IL-2. Unexpectedly, ILC2-intrinsic IL-33 activation was required for Treg cell accumulation invivo and was independent of ILC2 type 2 cytokines but partially dependent on direct co-stimulatory interactions via ICOSL-ICOS. IFN-γ inhibited ILC2 activation and Treg cell accumulation by IL-33 in infected tissue, as well as adipose tissue, where repression increased with aging and high-fat diet-induced obesity. IL-33 and ILC2s are central mediators of type 2 immune responses that promote tissue and metabolic homeostasis, and IFN-γ suppresses this pathway, likely to promote inflammatory responses and divert metabolic resources necessary to protect the host. Group 2 innate lymphoid cells (ILC2s) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis and contribute to tissue repair. Locksley and colleagues describe how the cytokines IL-33 and IFN-γ counter-regulate ILC2 activation to control Treg cell numbers and type 2 immune responses.
- Published
- 2014
48. Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo controlled, phase 2 trial
- Author
-
Gitelman, SE, Gottlieb, PA, Rigby, MR, Felner, EI, Willi, SM, Fisher, LK, Moran, A, Gottschalk, M, Moore, WV, Pinckney, A, Keyes-Elstein, L, Aggarwal, S, Phippard, D, Sayre, PH, Ding, L, Bluestone, JA, and Ehlers, MR
- Published
- 2014
49. Pathogenic conversion of Foxp3+T cells into TH17 cells in autoimmune arthritis
- Author
-
Komatsu, N, Okamoto, K, Sawa, S, Nakashima, T, Oh-Hora, M, Kodama, T, Tanaka, S, Bluestone, JA, and Takayanagi, H
- Subjects
hemic and immune systems ,chemical and pharmacologic phenomena - Abstract
Autoimmune diseases often result from an imbalance between regulatory T (T reg) cells and interleukin-17 (IL-17)-producing T helper (T H 17) cells; the origin of the latter cells remains largely unknown. Foxp3 is indispensable for the suppressive function of T reg cells, but the stability of Foxp3 has been under debate. Here we show that T H 17 cells originating from Foxp3 + T cells have a key role in the pathogenesis of autoimmune arthritis. Under arthritic conditions, CD25 lo Foxp3 + CD4 + T cells lose Foxp3 expression (herein called exFoxp3 cells) and undergo transdifferentiation into T H 17 cells. Fate mapping analysis showed that IL-17-expressing exFoxp3 T (exFoxp3 T H 17) cells accumulated in inflamed joints. The conversion of Foxp3 + CD4 + T cells to T H 17 cells was mediated by synovial fibroblast-derived IL-6. These exFoxp3 T H 17 cells were more potent osteoclastogenic T cells than were naive CD4 + T cell-derived T H 17 cells. Notably, exFoxp3 T H 17 cells were characterized by the expression of Sox4, chemokine (C-C motif) receptor 6 (CCR6), chemokine (C-C motif) ligand 20 (CCL20), IL-23 receptor (IL-23R) and receptor activator of NF-κB ligand (RANKL, also called TNFSF11). Adoptive transfer of autoreactive, antigen-experienced CD25 lo Foxp3 + CD4 + T cells into mice followed by secondary immunization with collagen accelerated the onset and increased the severity of arthritis and was associated with the loss of Foxp3 expression in the majority of transferred T cells. We observed IL-17 + Foxp3 + T cells in the synovium of subjects with active rheumatoid arthritis (RA), which suggests that plastic Foxp3 + T cells contribute to the pathogenesis of RA. These findings establish the pathological importance of Foxp3 instability in the generation of pathogenic T H 17 cells in autoimmunity.
- Published
- 2014
50. CD28-inducible transcription factor DEC1 is required for efficient autoreactive CD4+T cell response
- Author
-
Martínez-Llordella, M, Esensten, JH, Bailey-Bucktrout, SL, Lipsky, RH, Marini, A, Chen, J, Mughal, M, Mattson, MP, Taub, DD, and Bluestone, JA
- Abstract
During the initial hours after activation, CD4+T cells experience profound changes in gene expression. Co-stimulation via the CD28 receptor is required for efficient activation of naive T cells. However, the transcriptional consequences of CD28 co-stimulation are not completely understood. We performed expression microarray analysis to elucidate the effectsof CD28 signals on the transcriptome of activated T cells. We show that the transcription factor DEC1 is highly induced in a CD28-dependent manner upon T cell activation, is involved in essential CD4+effector T cell functions, and participates in the transcriptional regulation of several T cell activation pathways, including a large group of CD28-regulated genes. Antigen-specific, DEC1-deficient CD4+T cells have cell-intrinsic defects in survival and proliferation. Furthermore, we found that DEC1 is required for the development of experimental autoimmune encephalomyelitis because of its critical role in the production of the proinflammatory cytokines GM-CSF, IFN-γ, and IL-2. Thus, we identify DEC1 as a critical transcriptional mediator in the activation of naive CD4+T cells that is required for the development of a T cell-mediated autoimmune disease. © 2013 Martínez-Llordella et al.
- Published
- 2013
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.