116 results on '"Murali-Krishna, Kaja"'
Search Results
102. Prolonged presence of effector‐memory CD8 T cells in the central nervous system after dengue virus encephalitis.
- Author
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Most, Robbert G. van der, Murali‐Krishna, Kaja, and Ahmed, Rafi
- Abstract
Dengue virus infection in the central nervous system (CNS) of immunized mice results in a strong influx of CD8 T cells into the brain. Whereas the kinetics of the splenic antiviral response are conventional, i.e. expansion followed by a rapid drop in the frequency of specific CD8 T cells, dengue virus‐specific CD8 T cells are retained in the CNS at a high frequency. These CD8 T cells display a partially activated phenotype (CD69high, Ly‐6A/Ehigh, CD62Llow), characteristic for effector‐memory T cells. CD43 expression, visualized by staining with the 1B11 mAb, decreased in time, suggesting that these persisting CD8 T cells differentiated into memory cells. These data add to the growing evidence implicating the CNS as a non‐lymphoid tissue capable of supporting prolonged T cell survival/maintenance. [ABSTRACT FROM PUBLISHER]
- Published
- 2003
- Full Text
- View/download PDF
103. Interleukin-4 acts at the locus of the antigen-presenting dendritic cell to counter-regulate cytotoxic CD8+ T-cell responses.
- Author
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King, Cecile, Mueller Hoenger, Regula, Malo Cleary, Mary, Murali-Krishna, Kaja, Ahmed, Rafi, King, Ernest, and Sarvetnick, Nora
- Subjects
INTERLEUKIN-4 ,ANTIGEN presenting cells ,T cells - Abstract
The mechanism underlying suppression of immune responses by interleukin-4 (IL-4) has remained unexplained. Here we show that the antigen-presenting dendritic cell is central to counter-regulation of autoimmune disease by IL-4. IL-4 acts at the locus of the dendritic cell to decrease the cytolytic T-cell response, preventing autoimmunity. Stimulation of cytotoxic precursors by antigen pulsed dendritic cells induces their differentiation but the process is blocked by IL-4. IL-4-influenced DC produce distinct effects on CD8
+ T cells depending on their state of activation. The molecular basis for this regulation is the alteration of the expression ratio of the costimulatory ligands B7.1/B7.2 on dendritic cells. Our findings demonstrate that B7.2 induces expansion of CD8+ T cells and B7.1 governs their acquisition of cytolytic activity. IL-4 influences the dendritic cell to elicit qualitative differences in T-cell responses, providing the basis for counter-regulation mediated by IL-4. [ABSTRACT FROM AUTHOR]- Published
- 2001
- Full Text
- View/download PDF
104. Generation of Trypanosoma cruzi-Specific CD8+T-Cell Immunity Is Unaffected by the Absence of Type I Interferon Signaling
- Author
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Martin, Diana L., Murali-Krishna, Kaja, and Tarleton, Rick L.
- Abstract
ABSTRACTTrypanosoma cruziis a protozoan parasite that causes human Chagas’ disease, a leading source of congestive heart failure in Central and South America. CD8+T cells are critical for control of T. cruziinfection, and CD8+T cells recognizing the immunodominant trans-sialidase gene-encoded peptide TSKB20 (ANYKFTLV) account for approximately 30% of the total CD8+T-cell population at the peak of infection in C57BL/6 mice. Type I interferons (IFN-I) are pleiotropic cytokines that play a critical role in both innate and adaptive immunity against a variety of infections, but their induction and their role in infection are dictated by the infectious agent. Because type I IFNs and IFN-responsive genes are evident early after T. cruziinfection of host cells, we examined the influence of IFN-I on the development of CD8+T-cell responses during this infection. Mice lacking the receptor for IFN-I (IFNARKO) and their wild-type counterparts both developed chronic infections and generated similar frequencies of immunodominant TSKB20- and subdominant TSKB18-specific CD8+T cells following T. cruziinfection. In contrast, peak TSKB20-specific CD8+T-cell responses generated during infection with vaccinia virus engineered to express TSKB20 were approximately 2.5-fold lower in IFNARKO mice than B6 mice, although after viral clearance, the frequencies of TSKB20-specific CD8+T cells stabilized at similar levels. Together, these data suggest that IFN-I induction and biology are dependent upon the microbial context and emphasize the need to investigate various infection models for a full understanding of CD8+T-cell development.
- Published
- 2010
- Full Text
- View/download PDF
105. Cutting edge: Progesterone regulates IFN-α production by plasmacytoid dendritic cells
- Author
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Grant C. Hughes, Edward A. Clark, Sunil Thomas, Murali-Krishna Kaja, and Chang Li
- Subjects
medicine.medical_treatment ,Immunology ,Human immunodeficiency virus (HIV) ,Medroxyprogesterone Acetate ,Biology ,medicine.disease_cause ,Vesicular stomatitis Indiana virus ,Steroid ,Mice ,Antiviral immunity ,Immunity ,medicine ,Animals ,Humans ,Immunology and Allergy ,Medroxyprogesterone acetate ,Cells, Cultured ,Progesterone ,Extramural ,Toll-Like Receptors ,Interferon-alpha ,TLR9 ,hemic and immune systems ,Dendritic Cells ,Immunity, Innate ,Blockade ,Mice, Inbred C57BL ,CpG Islands ,Female ,Vesicular Stomatitis ,Spleen ,medicine.drug - Abstract
Use of the progesterone (Pg) birth control depot medroxyprogesterone acetate (DMPA) increases a woman’s risk for sexually transmitted infection with HIV or HSV-2 via unknown mechanisms. Plasmacytoid dendritic cells (pDCs) are circulating and tissue-resident sentinels capable of making large quantities of IFN-α upon recognizing viruses through TLRs 7 and 9. In this study, we show that Pg inhibits TLR9-induced IFN-α production by human and mouse pDCs and that DMPA impairs TLR9- and virus-induced IFN-α production by pDCs in mice, providing a potential explanation for how DMPA impairs innate antiviral immunity in women. Pg failed to inhibit the Mda-5 pathway of IFN-α induction in dendritic cells, suggesting that Pg regulates select antiviral DC programs. This may occur through selective blockade of IFN regulatory factor-7 activation, a novel steroid action. Thus, through inhibition of TLR-mediated IFN-α production by pDCs, Pg may regulate antiviral immunity.
106. Functional and transcriptional heterogeneity within the massively expanding HLADR+CD38+ CD8 T cell population in acute febrile dengue patients.
- Author
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Singh, Prabhat, Bajpai, Prashant, Maheshwari, Deepti, Chawla, Yadya M., Saini, Keshav, Reddy, Elluri Seetharami, Gottimukkala, Kamalvishnu, Nayak, Kaustuv, Gunisetty, Sivaram, Aggarwal, Charu, Jain, Shweta, Verma, Chaitanya, Singla, Paras, Soneja, Manish, Wig, Naveet, Murali-Krishna, Kaja, and Chandele, Anmol
- Subjects
- *
T cells , *CELL populations , *CD8 antigen , *T cell receptors , *DENGUE , *DENGUE viruses , *T-cell exhaustion , *FENITROTHION - Abstract
CD8 T cells are important tools for protection against intracellularly replicating pathogens such as viruses. Previous studies showed that a discrete population of HLADR and CD38-expressing CD8 T cells expands massively during the acute febrile phase of human dengue virus infection--but very few of these cells secrete IFNγ upon in vitro stimulation with dengue peptides. To gain a better understanding of what other cytokines/chemokines do these massively expanding HLADR+CD38+ CD8 T cells express, we performed RNA seq of sorted HLADR+CD38+ CD8 T cell subsets after peptide stimulation. A majority of these peptide-stimulated HLADR+CD38+ CD8 T cells were CD69- IFNγ-, nearly a third were CD69+ IFNγ-, whereas very few (<10%) were CD69+ IFNγ+. The CD69- IFNγ- subset was enriched for the expression of key genes implicated in the negative regulation of T cell receptor (TCR) signaling and T-cell exhaustion, attraction of B cells and other lymphocytes, and cytokines related to Tc17/T-reg lineages or those that are implicated in immunosuppression/immunomodulatory and anti-inflammatory activities and angiogenesis. The CD69+ IFNγ- subset showed enriched transcription of key genes implicated in cytotoxic effector functions as well as costimulatory and signaling adaptors implicated in fine balancing of T cell receptor signaling. The CD69+ IFNγ+ subset largely shared the transcriptional profile with the CD69+ IFNγsubset--but with relatively more pronounced expression along with additional genes such as chemokines XCL1/XCL2. Our findings showing distinct functional subsets among these massively expanding CD8 T cells in dengue CD8 T cells warrant further studies to carefully examine the precise role of these T cell subsets in protection against dengue. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
107. Counting Antigen-Specific CD8 T Cells: A Reevaluation of Bystander Activation during Viral Infection
- Author
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Murali-Krishna, Kaja, Altman, John D, Suresh, M, Sourdive, David J.D, Zajac, Allan J, Miller, Joseph D, Slansky, Jill, and Ahmed, Rafi
- Published
- 1998
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108. Therapeutic vaccination against chronic viral infection: the importance of cooperation between CD4 + and CD8 + T cells
- Author
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Zajac, Allan J, Murali-Krishna, Kaja, Blattman, Joseph N, and Ahmed, Rafi
- Published
- 1998
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109. Human Effector and Memory CD8+ T Cell Responses to Smallpox and Yellow Fever Vaccines
- Author
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Miller, Joseph D., van der Most, Robbert G., Akondy, Rama S., Glidewell, John T., Albott, Sophia, Masopust, David, Murali-Krishna, Kaja, Mahar, Patryce L., Edupuganti, Srilatha, Lalor, Susan, Germon, Stephanie, Del Rio, Carlos, Mulligan, Mark J., Staprans, Silvija I., Altman, John D., Feinberg, Mark B., and Ahmed, Rafi
- Subjects
- *
T cells , *PREVENTIVE medicine , *LYMPHOCYTES , *YELLOW fever , *SMALLPOX - Abstract
Summary: To explore the human T cell response to acute viral infection, we performed a longitudinal analysis of CD8+ T cells responding to the live yellow fever virus and smallpox vaccines—two highly successful human vaccines. Our results show that both vaccines generated a brisk primary effector CD8+ T cell response of substantial magnitude that could be readily quantitated with a simple set of four phenotypic markers. Secondly, the vaccine-induced T cell response was highly specific with minimal bystander effects. Thirdly, virus-specific CD8+ T cells passed through an obligate effector phase, contracted more than 90% and gradually differentiated into long-lived memory cells. Finally, these memory cells were highly functional and underwent a memory differentiation program distinct from that described for human CD8+ T cells specific for persistent viruses. These results provide a benchmark for CD8+ T cell responses induced by two of the most effective vaccines ever developed. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
110. Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response.
- Author
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Patel A, Kumar S, Lai L, Chakravarthy C, Valanparambil R, Reddy ES, Gottimukkala K, Bajpai P, Raju DR, Edara VV, Davis-Gardner ME, Linderman S, Dixit K, Sharma P, Mantus G, Cheedarla N, Verkerke HP, Frank F, Neish AS, Roback JD, Davis CW, Wrammert J, Ahmed R, Suthar MS, Sharma A, Murali-Krishna K, Chandele A, and Ortlund EA
- Abstract
A detailed understanding of the molecular features of the neutralizing epitopes developed by viral escape mutants is important for predicting and developing vaccines or therapeutic antibodies against continuously emerging SARS-CoV-2 variants. Here, we report three human monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during first wave of pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, but poorly neutralized Beta and completely failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these three mAbs in complex with trimeric spike protein showed that all three mAbs are involved in bivalent spike binding with two mAbs targeting class-1 and one targeting class-4 Receptor Binding Domain (RBD) epitope. Comparison of immunogenetic makeup, structure, and function of these three mAbs with our recently reported class-3 RBD binding mAb that potently neutralized all SARS-CoV-2 variants revealed precise antibody footprint, specific molecular interactions associated with the most potent multi-variant binding / neutralization efficacy. This knowledge has timely significance for understanding how a combination of certain mutations affect the binding or neutralization of an antibody and thus have implications for predicting structural features of emerging SARS-CoV-2 escape variants and to develop vaccines or therapeutic antibodies against these.
- Published
- 2022
- Full Text
- View/download PDF
111. Generation of Trypanosoma cruzi-specific CD8+ T-cell immunity is unaffected by the absence of type I interferon signaling.
- Author
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Martin DL, Murali-Krishna K, and Tarleton RL
- Subjects
- Animals, CD8-Positive T-Lymphocytes physiology, Female, Immunity, Cellular immunology, Interferon Regulatory Factors genetics, Interferon Regulatory Factors immunology, Interferon Regulatory Factors physiology, Interferon Type I immunology, Lymphocyte Activation immunology, Lymphocyte Activation physiology, Male, Mice, Mice, Inbred C57BL, Receptors, Interferon immunology, Receptors, Interferon physiology, Signal Transduction immunology, Signal Transduction physiology, CD8-Positive T-Lymphocytes immunology, Chagas Disease immunology, Immunity, Cellular physiology, Interferon Type I physiology, Trypanosoma cruzi immunology
- Abstract
Trypanosoma cruzi is a protozoan parasite that causes human Chagas' disease, a leading source of congestive heart failure in Central and South America. CD8+ T cells are critical for control of T. cruzi infection, and CD8+ T cells recognizing the immunodominant trans-sialidase gene-encoded peptide TSKB20 (ANYKFTLV) account for approximately 30% of the total CD8+ T-cell population at the peak of infection in C57BL/6 mice. Type I interferons (IFN-I) are pleiotropic cytokines that play a critical role in both innate and adaptive immunity against a variety of infections, but their induction and their role in infection are dictated by the infectious agent. Because type I IFNs and IFN-responsive genes are evident early after T. cruzi infection of host cells, we examined the influence of IFN-I on the development of CD8+ T-cell responses during this infection. Mice lacking the receptor for IFN-I (IFNARKO) and their wild-type counterparts both developed chronic infections and generated similar frequencies of immunodominant TSKB20- and subdominant TSKB18-specific CD8+ T cells following T. cruzi infection. In contrast, peak TSKB20-specific CD8+ T-cell responses generated during infection with vaccinia virus engineered to express TSKB20 were approximately 2.5-fold lower in IFNARKO mice than B6 mice, although after viral clearance, the frequencies of TSKB20-specific CD8+ T cells stabilized at similar levels. Together, these data suggest that IFN-I induction and biology are dependent upon the microbial context and emphasize the need to investigate various infection models for a full understanding of CD8+ T-cell development.
- Published
- 2010
- Full Text
- View/download PDF
112. Virus binding to a plasma membrane receptor triggers interleukin-1 alpha-mediated proinflammatory macrophage response in vivo.
- Author
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Di Paolo NC, Miao EA, Iwakura Y, Murali-Krishna K, Aderem A, Flavell RA, Papayannopoulou T, and Shayakhmetov DM
- Subjects
- Adenoviridae immunology, Adenoviridae metabolism, Animals, Carrier Proteins metabolism, Genetic Vectors immunology, Genetic Vectors metabolism, Immunity, Innate, Integrin beta3 immunology, Integrin beta3 metabolism, Interleukin-1alpha metabolism, Macrophages cytology, Macrophages metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, NLR Family, Pyrin Domain-Containing 3 Protein, Receptors, Interleukin-1 metabolism, Spleen cytology, Spleen immunology, Spleen metabolism, Toll-Like Receptor 9 metabolism, Carrier Proteins immunology, Interleukin-1alpha immunology, Macrophages immunology, Receptors, Interleukin-1 immunology, Toll-Like Receptor 9 immunology
- Abstract
The recognition of viral components by host pattern-recognition receptors triggers the induction of the antiviral innate immune response. Toll-like receptor 9 (TLR9) and NLRP3 inflammasome were shown to be the principal specific sensors of viral double-stranded DNA. Here we present evidence that macrophages in vivo activated an innate immune response to a double-stranded DNA virus, adenovirus (Ad), independently of TLR9 or NLRP3 inflammasome. In response to Ad, macrophage-derived IL-1 alpha triggered IL-1RI-dependent production of a defined set of proinflammatory cytokines and chemokines. The IL-1 alpha-mediated response required a selective interaction of virus arginine-glycine-aspartic acid (RGD) motifs with macrophage beta(3) integrins. Thus, these data identify IL-1 alpha-IL-1RI as a key pathway allowing for the activation of proinflammatory responses to the virus, independently of its genomic nucleic acid recognition.
- Published
- 2009
- Full Text
- View/download PDF
113. IFN-gamma induces the erosion of preexisting CD8 T cell memory during infection with a heterologous intracellular bacterium.
- Author
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Dudani R, Murali-Krishna K, Krishnan L, and Sad S
- Subjects
- Animals, Antigens immunology, Cells, Cultured, Interferon-alpha immunology, Interferon-alpha metabolism, Interferon-gamma metabolism, Listeria monocytogenes immunology, Listeria monocytogenes pathogenicity, Mice, Mycobacterium bovis immunology, Mycobacterium bovis pathogenicity, Salmonella typhimurium immunology, Salmonella typhimurium pathogenicity, Spleen immunology, Spleen metabolism, Time Factors, CD8-Positive T-Lymphocytes immunology, Immunologic Memory immunology, Interferon-gamma immunology, Listeriosis immunology, Salmonella Infections immunology, Tuberculosis immunology
- Abstract
Memory T cells are critical for the control of intracellular pathogens and require few signals for maintenance; however, erosion of established preexisting memory CD8(+) T cells has been shown to occur during infection with heterologous viral infections. We evaluated whether this also occurs during infection with various intracellular bacteria and what mechanisms may be involved. We demonstrate that erosion of established memory is also induced during infection of mice with various intracellular bacteria, such as Listeria monocytogenes, Salmonella typhimurium, and Mycobacterium bovis (bacillus Calmette-Guérin). The extent of erosion of established CD8(+) T cell memory was dependent on the virulence of the heterologous pathogen, not persistence. Furthermore, when antibiotics were used to comprehensively eliminate the heterologous pathogen, the numbers of memory CD8(+) T cells were not restored, indicating that erosion of preexisting memory CD8(+) T cells was irreversible. Irrespective of the initial numbers of memory CD8(+) T cells, challenge with the heterologous pathogen resulted in a similar extent of erosion of memory CD8(+) T cells, suggesting that cellular competition was not responsible for erosion. After challenge with the heterologous pathogen, effector memory CD8(+) T cells were rapidly eliminated. More importantly, erosion of preexisting memory CD8(+) T cells was abrogated in the absence of IFN-gamma. These studies help reveal the paradoxical role of IFN-gamma. Although IFN-gamma promotes the control of intracellular bacterial replication during primary infection, this comes at the expense of erosion of preexisting memory CD8(+) T cells in the wake of infection with heterologous pathogens.
- Published
- 2008
- Full Text
- View/download PDF
114. IL-12 and type-I IFN synergize for IFN-gamma production by CD4 T cells, whereas neither are required for IFN-gamma production by CD8 T cells after Listeria monocytogenes infection.
- Author
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Way SS, Havenar-Daughton C, Kolumam GA, Orgun NN, and Murali-Krishna K
- Subjects
- Adoptive Transfer, Animals, CD4-Positive T-Lymphocytes transplantation, Interferon Type I genetics, Interferon-gamma metabolism, Interleukin-12 genetics, Mice, Mice, Mutant Strains, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Interferon Type I physiology, Interleukin-12 physiology, Listeria monocytogenes, Listeriosis immunology
- Abstract
Differentiation of Ag-specific T cells into IFN-gamma producers is essential for protective immunity to intracellular pathogens. In addition to stimulation through the TCR and costimulatory molecules, IFN-gamma production is thought to require other inflammatory cytokines. Two such inflammatory cytokines are IL-12 and type I IFN (IFN-I); both can play a role in priming naive T cells to produce IFN-gamma in vitro. However, their role in priming Ag-specific T cells for IFN-gamma production during experimental infection in vivo is less clear. In this study, we examine the requirements for IL-12 and IFN-I, either individually or in combination, for priming Ag-specific T cell IFN-gamma production after Listeria monocytogenes (Lm) infection. Surprisingly, neither individual nor combined defects in IL-12 or IFN-I signaling altered IFN-gamma production by Ag-specific CD8 T cells after Lm infection. In contrast, individual defects in either IL-12 or IFN-I signaling conferred partial ( approximately 50%) reductions, whereas combined deficiency in both IL-12 and IFN-I signaling conferred more dramatic (75-95%) reductions in IFN-gamma production by Ag-specific CD4 T cells. The additive effects of IL-12 and IFN-I signaling on IFN-gamma production by CD4 T cells were further demonstrated by adoptive transfer of transgenic IFN-IR(+/+) and IFN-IR(-/-) CD4 T cells into normal and IL-12-deficient mice, and infection with rLm. These results demonstrate an important dichotomy between the signals required for priming IFN-gamma production by CD4 and CD8 T cells in response to bacterial infection.
- Published
- 2007
- Full Text
- View/download PDF
115. Rapid demethylation of the IFN-gamma gene occurs in memory but not naive CD8 T cells.
- Author
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Kersh EN, Fitzpatrick DR, Murali-Krishna K, Shires J, Speck SH, Boss JM, and Ahmed R
- Subjects
- Animals, Azacitidine pharmacology, CD8-Positive T-Lymphocytes chemistry, CD8-Positive T-Lymphocytes drug effects, Cells, Cultured, CpG Islands, DNA chemistry, DNA genetics, Gene Expression Regulation drug effects, Immunity, Innate drug effects, Immunologic Memory drug effects, Immunologic Memory genetics, Interferon-gamma biosynthesis, Interferon-gamma chemistry, Interleukin-2 genetics, Mice, Promoter Regions, Genetic genetics, RNA, Messenger genetics, Time Factors, Transcription, Genetic genetics, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, DNA Methylation, Immunity, Innate immunology, Immunologic Memory immunology, Interferon-gamma genetics
- Abstract
DNA methylation is an epigenetic mechanism of gene regulation. We have determined that specific modifications in DNA methylation at the IFN-gamma locus occur during memory CD8 T cell differentiation in vivo. Expression of the antiviral cytokine IFN-gamma in CD8 T cells is highly developmental stage specific. Most naive cells must divide before they express IFN-gamma, while memory cells vigorously express IFN-gamma before cell division. Ag-specific CD8 T cells were obtained during viral infection of mice and examined directly ex vivo. Naive cells had an IFN-gamma locus with extensive methylation at three specific CpG sites. An inhibitor of methylation increased the amount of IFN-gamma in naive cells, indicating that methylation contributes to the slow and meager production of IFN-gamma. Effectors were unmethylated and produced large amounts of IFN-gamma. Interestingly, while memory cells were also able to produce large amounts of IFN-gamma, the gene was partially methylated at the three CpG sites. Within 5 h of antigenic stimulation, however, the gene was rapidly demethylated in memory cells. This was independent of DNA synthesis and cell division, suggesting a yet unidentified demethylase. Rapid demethylation of the IFN-gamma promoter by an enzymatic factor only in memory cells would be a novel mechanism of differential gene regulation. This differentiation stage-specific mechanism reflects a basic immunologic principle: naive cells need to expand before becoming an effective defense factor, whereas memory cells with already increased precursor frequency can rapidly mount effector functions to eliminate reinfecting pathogens in a strictly Ag-dependent fashion.
- Published
- 2006
- Full Text
- View/download PDF
116. Proliferation and differentiation of CD8+ T cells in the absence of IL-2/15 receptor beta-chain expression or STAT5 activation.
- Author
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Teague RM, Tempero RM, Thomas S, Murali-Krishna K, and Nelson BH
- Subjects
- Antineoplastic Agents pharmacology, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes drug effects, Cell Division drug effects, Cell Division immunology, In Vitro Techniques, Interleukin-15 immunology, Interleukin-15 metabolism, Interleukin-2 immunology, Interleukin-2 metabolism, Interleukin-2 pharmacology, Receptors, Interleukin-15, STAT5 Transcription Factor, CD8-Positive T-Lymphocytes immunology, Cell Differentiation immunology, DNA-Binding Proteins immunology, Milk Proteins, Receptors, Interleukin-2 immunology, Trans-Activators immunology
- Abstract
Major gains in the efficacy of T cell-based therapies for cancer and infectious diseases could be realized through improved understanding of the signals that control expansion and differentiation of CD8(+) cytolytic T cells. IL-2, IL-15, and the downstream transcription factor STAT5 have all been implicated as important regulators of these processes, yet there are conflicting data regarding their contribution to in vivo T cell responses. We used a murine adoptive T cell transfer model to examine the contribution of IL-2 and IL-15 signaling to the proliferation and differentiation of naive, CD8(+) T cells bearing an OVA-specific TCR transgene (OT-I). OT-I T cells failed to express the high affinity IL-2R (CD25) while proliferating in vivo, irrespective of the mode of Ag delivery. Moreover, OT-I T cells rendered genetically deficient in the shared IL-2/IL-15Rbeta subunit (IL-2Rbeta) demonstrated normal Ag-induced proliferation and cytolytic activity in vivo. Accordingly, activation of STAT5 was not detected in proliferating IL-2Rbeta-deficient OT-I T cells, thus implicating a STAT5-independent cytokine or costimulatory pathway in this process. Even though IL-2 and IL-15 were dispensable for CD8(+) T cell proliferation, systemic infusion of IL-2 nevertheless promoted the expansion of OT-I T cells in vivo. Thus, IL-2 and IL-15 signals are not essential for CD8(+) T cell proliferation or differentiation, but IL-2 can promote supraphysiological expansion when supplied exogenously. These findings challenge current models that place CD8(+) T cell proliferation under the control of STAT5-dependent cytokines and suggest new approaches to the therapeutic manipulation of T cell numbers in vivo.
- Published
- 2004
- Full Text
- View/download PDF
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