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Programmed death-1 (PD-1) blockade during chronic Simian immunodeficiency virus (SIV) infection results in restoration of CD8 T-cell function and enhances viral control. Here, we tested the therapeutic benefits of PD-1 blockade administered soon after antiretrovial therapy (ART) interruption (ATI) by treating SIV-infected and ARTsuppressed macaques with either an anti-PD-1 antibody (n = 7) or saline (n = 4) at 4 wk after ATI. Following ATI, the plasma viremia increased rapidly in all animals, and the frequency of SIV-specific CD8 T cells also increased in some animals. PD-1 blockade post ATI resulted in higher proliferation of total memory CD8 and CD4 T cells and natural killer cells. PD-1 blockade also resulted in higher proliferation of SIVspecific CD8 T cells and promoted their differentiation toward better functional quality. Importantly, four out of the seven anti-PD-1 antibody-treated animals showed a rapid decline in plasma viremia by 100-to 2300-fold and this was observed only in animals that showed measurable SIV-specific CD8 T cells post PD-1 blockade. These results demonstrate that PD-1 blockade following ATI can significantly improve the function of anti-viral CD8 T cells and enhance viral control and strongly suggests its potential synergy with other immunotherapies that induce functional CD8 T-cell response under ART. These results have important implications for HIV cure research. [ABSTRACT FROM AUTHOR]

Inhibitory receptors play a crucial role in regulating CD8 T-cell function during chronic viral infection. T-cell Ig- and mucin-domain--containing molecule-3 (Tim-3) is well known to negatively regulate T-cell responses, but its role in CD8 T-cell exhaustion during chronic infection in vivo remains unclear. In this study, we document coregulation of CD8 T cell exhaustion by Tim-3 and PD-1 during chronic lymphocytic choriomeningitis virus infection. Whereas Tim-3 was only transiently expressed by CD8 T cells after acute infection, virus-specific CD8 T cells retained high Tim-3 expression throughout chronic infection. The majority (approximately 65% to 80%) of lymphocytic choriomeningitis virus--specific CD8 T cells in lymphoid and nonlymphoid organs coexpressed Tim-3 and PD-1. This coexpression of Tim-3 and PD-1 was associated with more severe CD8 T-cell exhaustion in terms of proliferation and secretion of effector cytokines such as IFN-[gamma], TNF-[alpha], and IL-2. Interestingly, CD8 T cells expressing both inhibitory receptors also produced the suppressive cytokine IL-10. Most importantly, combined blockade of Tim-3 and PD-1 pathways in vivo synergistically improved CD8 T cell responses and viral control in chronically infected mice. Taken together, our study defines a parameter for determining the severity of CD8 T cell dysfunction and for identifying virus-specific CD8 T cells that produce IL-10, and shows that targeting both PD-1 and Tim-3 is an effective immune strategy for treating chronic viral infections. doi/ 10.1073/pnas.1009731107

The ability to induce durable transplantation tolerance predictably and consistently in the clinic is a highly desired but elusive goal. Progress is hampered by lack of appropriate experimental models in which to study resistance to transplantation tolerance. Here, we demonstrate that T helper 1-associated T box 21 transcription factor (Tbet) KO recipients exhibit allograft tolerance resistance specifically mediated by IL-17-producing CD8 T (T17) cells. Neutralization of IL-17 facilitates long-term cardiac allograft survival with combined T cell co-stimulation (CD28-CD80/86 and CD154-CD40) blockade in Tbet KO recipients. We have used this T17-biased Tbet KO model of allograft tolerance resistance to study the impact of targeting a T cell-costimulatory pathway, and demonstrate that targeting T cell Ig and mucin domain-1 (Tim-1) with anti-Tim-1 overcomes this resistance by specifically inhibiting the pathogenic IL-17-producing CD8 T17 cells. These data indicate that in the absence of Th1 immunity, CD8 T17 alloreactivity constitutes a barrier to transplantation tolerance. Targeting TIM-1 provides an approach to overcome resistance to tolerance in clinical transplantation. costimulation | IL-17 | rejection | immunosuppression

Suppression of T-cell responses by host-derived regulatory factors is a key event leading to viral persistence. Antibody blockade of either IL-10 or programmed death-ligand 1 (PD-L1) during viral persistence enhances T-cell function and reduces viral titers. Because blockade of these immunoregulatory networks represents a powerful approach to establish immune control during persistent infection, it is important to determine whether these immunoinhibitory factors act independently or jointly and if combined blockade of these factors further enhances T-cell immunity and viral clearance. Herein, we demonstrate that the IL-10 and PD-L1 immunosuppressive pathways are mechanistically distinct. As a result, simultaneous blockade of IL-10 and PD-L1 was significantly more effective in restoring antiviral T-cell responses than blockade of either alone, and led to substantially enhanced control of an established persistent viral infection. Thus, combinatorial blockade of multiple immune-regulatory molecules may ultimately restore the T-cell responses required to tip the balance from viral persistence to immune-mediated control or elimination of persistent infection. T-cell exhaustion | virus persistence | functional restoration | immune regulation | immunosuppression

Programmed death-1 (PD-1) regulates T cell exhaustion during chronic infections. Blocking the PD-1:PD-ligand (PD-L) pathway reinvigorates exhausted CD8 T cells. Exactly how blocking PD-1:PD-L interactions improves T cell immunity, however, remains unclear. PD-1:PD-L blockade could reprogram all exhausted T cells to become antiviral effectors. Alternatively, this blockade might selectively expand a subset of exhausted T cells. We have identified two subpopulations of exhausted CD8 T cells during chronic viral infection in mice. One subset of exhausted CD8 T cells is rescued by [alpha]PD-L1 blockade, whereas the other subset appears more terminally differentiated and responds poorly to PD-1:PD-L blockade. Blocking PD-1:PD-L interactions reduces spontaneous apoptosis and enhances expansion and protective immunity of the rescuable subset, but not the more terminally differentiated subset of exhausted CD8 T cells. These results have implications for predicting clinical responses to PD-1-based therapeutic interventions and for understanding T cell dynamics during persisting infections. chronic infection | lymphocytic choriomeningitis virus | T cell exhaustion | PD-1 | T cell memory

The PD-1 costimulatory receptor inhibits T cell receptor signaling upon interacting with its ligands PD-L1 and PD-L2. The PD-1/PD-L pathway is critical in maintaining self-tolerance, in this study, we examined the role of PD-1 in a mouse model of acute infection with Histoplasma capsulatum, a major human pathogenic fungus. In a lethal model of histoplasmosis, all PD-1-deficient mice survived infection, whereas the wild-type mice died with disseminated disease. PD-L expression on macrophages and splenocytes was up-regulated during infection, and macrophages from infected mice inhibited in vitro T cell activation. Of interest, antibody blocking of PD-1 significantly increased survival of lethally infected wild-type mice. Thus, our studies extend the role of the PD-1/PD-L pathway in regulating antimicrobial immunity to fungal pathogens. The results show that the PD-1/PD-L pathway has a key role in the regulation of antifungal immunity, and suggest that manipulation of this pathway represents a strategy of immunotherapy for histoplasmosis. costimulation | fungal infection | programmed death-1

Many chronic viral infections are marked by pathogen persistence and a generalized immunosuppression. The exact mechanisms by which this occurs are still unknown. Using a mouse model of persistent lymphocytic choriomeningitis virus (LCMV) infection, we demonstrate viral targeting of fibroblastic reticular cells (FRC) in the lymphoid organs. The FRC stromal networks are critical for proper lymphoid architecture and function. High numbers of FRC were infected by LCMV clone 13, which causes a chronic infection, whereas few were infected by the acute strain, LCMV Armstrong. The function of the FRC conduit network was altered after clone 13 infection by the action of [CD8.sup.+] T cells. Importantly, expression of the inhibitory programmed death ligand 1, which was up-regulated on FRC after infection, reduced early [CD8.sup.+] T cell-mediated immunopathology and prevented destruction of the FRC architecture in the spleen. Together, this reveals an important tropism during a persistent viral infection. These data also suggest that the inhibitory PD-1 pathway, which likely evolved to prevent excessive immunopathology, may contribute to viral persistence in FRC during chronic infection. immunopathology | stromal cells | viral infection

Both positive and negative regulatory roles have been suggested for the B7 family member PD-L1(BT-H1). PD-L1 is expressed on antigen-presenting cells (APCs), activated T cells, and a variety of tissues, but the functional significance of PD-L1 on each cell type is not yet clear. To dissect the functions of PD-L1 in vivo, we generated PD-Ll-deficient (PD-L[1.sup.-/-]) mice. CD[4.sup.+] and CD[8.sup.+] T cell responses were markedly enhanced in pD-L[1.sup.-/-] mice compared with wild-type mice in vitro and in vivo. PD-L[1.sup.-/-] dendritic cells stimulated greater wild-type CD[4.sup.+] T cell responses than wild-type dendritic cells, and PD-L[1.sup.-/-] CD[4.sup.+] T cells produced more cytokines than wild-type CD[4.sup.+] T cells in vitro, demonstrating an inhibitory role for PD-L1 on APCs and T cells. In vivo CD[8.sup.+] T cell responses also were significantly enhanced, indicating that PD-L1 has a role in limiting the expansion or survival of CD[8.sup.+] T cells. Studies using the myelin oligodendrocyte model of experimental autoimmune encephalomyelitis showed that PD-L1 on T cells and in host tissues limits responses of self-reactive CD[4.sup.+] T cells in vivo. PD-L1 deficiency converted the 129S4/SvJae strain from a resistant to experimental autoimmune encephalomyelitis-susceptible strain. Transfer of encephalitogenic T cells from wild-type mice into PD-L[1.sup.-/-] recipients led to exacerbated disease. Disease was even more severe in PD-L[1.sup.-/-] recipients of PD-L[1.sup.-/-] T cells. These results demonstrate that PD-L1 on T cells, APCs, and host tissue inhibits naive and effector T cell responses and plays a critical role in T cell tolerance.

The function of CD48 is determined by generating mice deficient in CD48 expression. The results of the experiment show that CD48 plays a crucial role in T cell activation through the T receptor cell/CD3 complex. Reduced proliferation in response to stimulation with lectins, alloantigen and anti-CD3 mAb were observed from the T cells of CD48-deficient mice. The use of phorbol ester phorbol 12-Myristate 13-Acetate as a costimulatory signal instead of antigen-presenting cells resulted in impairments. T cell responses were reconstituted with the addition of irradiated APCs.

Herein we describe the molecular characterization of the human leukocyte activation antigen CD100 and identify it as the first semaphorin, to our knowledge, in the immune system. Semaphorins have recently been described as neuronal chemorepellants that direct pioneering neurons during nervous system development. In this study we demonstrate that CD100 induces B cells to aggregate and improves their viability in vitro. We show that CD100 modifies CD40-CD40L B-cell signaling by augmenting B-cell aggregation and survival and down-regulating CD23 expression. Thus, these results suggest that semaphorins as exemplified by CD100 also play a functional role in the immune system.

The strong expression of major histocompatibility complex and the minor expression of some adhesion and B7 costimulatory molecules do not present alloantigen efficiently in humans follicular lymphoma cells. However, in vitro, the activation of follicular lymphoma cells via CD40 pathway provides signals to T cells to become efficient alloantigen-presenting cells. This evidence implies that expression of major histocompatibility complex and expression of multiple adhesion and costimulatory molecules are required for the correction of defective tumor immunity.

Cross-linking of the T-cell surface molecule CTLA4 enables clonal deletion of human T lymphocytes, that have been activated previously. This apoptosis is regulated by antigen, as revealed by the necessity for a concomitant signal T-cell receptor signal. These T-cells can be deleted by regulating the signal pathway. The ligand that causes cell death is expressed on LBL-DR7 cells.

Human leukotriene (LT) C4 synthase, an integral membrane protein, connects LTA4 and reduced glutathione to form a proinflammatory mediator, LTC4. Fluorescence-linked immunoassay helps expression cloning of cDNA for human LTC4 synthase from a KG-1 cDNA expression library in COS-7 cells. Step-wise resolution identifies individual clones having high LTC4 synthase activity. Amino acid sequence of LTC4 synthase exhibits homology to the 5-lipoxygenase activating protein (FLAP). The peptide structure reveals three transmembrane domains that are superimposable on those of FLAP. The difference between LTC4 synthase and known GSH S-transferases suggest that it belongs to a distinct gene family.

Activation of self-reactive T cells may depend on aberrant B7 expression on peripheral tissues in mice. Several T-cell mediated autoimmune disease may involve extraordinary expression of costimulatory receptors. Transgenic mice expressing the costimulatory mouse molecule B7-1, a ligand for the CD28 receptor, have been analyzed.

An analysis of CTLA-4 counterreceptors reveals that a pair of this type of counterreceptors are expressed on stimulated human B lymphocytes BB-1, B7-3 and B7-2. The pair can costimulate the T-cell, and their costimulatory signals may be necessary for the production of an immune response.

Tetanus toxoid peptide antigen in a human antigen-specific construct, when presented by cells cotransfected with HLA-DR7 and B7, yields interleukin 2 generation and optimal T-cell proliferation. Antigen presentation without B7 coactivation causes T-cell clonal energy. Antigen-specific clonal tolerance can be stimulated in human T cells already sensitized to antigen.

A study shows that mouse sarcoma cells that were genetically designed to offer antigent specific and costimulatory T-cell activation signals activate potent tumor-specific CD4+T cells that result in the rejection of engineered and wild-type neoplastic cells. Results portray the influence of the B7 activation molecule in this activation and rejection, and offer a theoretical foundation for immunotherapy of established tumors.

The identification of a murine lymphocyte protein, termed sgp-60, as the homologue of CD48 was reported. The murine glycoprotein is expressed on all lymphocytes of both T- and B-cell origin. Protein sequencing of the sgp-60 antigen and gene transfection experiments demonstrate that sgp-60 is identical to the CD48 antigen, which is also called Blast-1 in humans, BCM1 in mice and OX-45 in rats.

A hamster-anti-murine B7 (mB7) monoclonal antibody (mAb) was generated. The mAb recognizes a protein with an apparent molecular mass of 60 kDa. With this mAb the expression and function of mB7 by normal and transformed cells were characterized. The results indicate that mB7 is the major costimulatory molecule expressed by peritoneal exudate cells and that there may be other molecules besides mB7 that can costimulate the activation of CD4+ T cells.

The costimulatory role of murine B7 (mB7) antigen for the activation of murine CD4 T lymphocytes through the T-cell receptor/CD3 complex was reported. Murine B7 antigen modulated the normal pathway of T-cell expansion by enhancing the production of interleukin 2 and expression of its receptor. Experiments showed Chinese ovary hamster cells transfected with mB7 combined with anti-CD3 monoclonal antibody and Con A-induced T cell activation that led to the production of T cells. This finding indicated the specificity of the effects of mB7.

Immunotherapy using checkpoint-blocking antibodies against PD-1 has produced impressive results in a wide range of cancers. However, the response remains heterogeneous among patients. We used noninvasive immuno-positron emission tomography (PET), using 89Zr-labeled PEGylated single-domain antibody fragments (nanobodies or VHHs), to explore the dynamics and distribution of intratumoral CD8+ T cells and CD11b+ myeloid cells in response to anti–PD-1 treatment in the MC38 colorectal mouse adenocarcinoma model. Responding and nonresponding tumors showed consistent differences in the distribution of CD8+ and CD11b+ cells. Anti–PD-1 treatment mobilized CD8+ T cells from the tumor periphery to a more central location. Only those tumors fully infiltrated by CD8+ T cells went on to complete resolution. All tumors contained CD11b+ myeloid cells from the outset of treatment, with later recruitment of additional CD11b+ cells. As tumors grew, the distribution of intratumoral CD11b+ cells became more heterogeneous. Shrinkage of tumors in responders correlated with an increase in the CD11b+ population in the center of the tumors. The changes in distribution of CD8+ and CD11b+ cells, as assessed by PET, served as biomarkers to gauge the efficacy of anti–PD-1 treatment. Single-cell RNA sequencing of RNA from intratumoral CD45+ cells showed that CD11b+ cells in responders and nonresponders were markedly different. The responders exhibited a dominant population of macrophages with an M1-like signature, while the CD45+ population in the nonresponders displayed an M2-like transcriptional signature. Thus, by using immuno-PET and single-cell RNA sequencing, we show that anti–PD-1 treatment not only affects interactions of CD8+ T cells with the tumor but also impacts the intratumoral myeloid compartment. [ABSTRACT FROM AUTHOR]

Anti-Porimin (Pro-oncosis receptor inducing membrane injury mAb mediates oncosis-like cell death in Jurkat cells. Porimin cDNA was isolated from a Jurkat cell cDNA library by COS cell-expression cloning. The 3,337-bp cDNA has an ORF of 567 bp, encoding a type I transmembrane protein of 189 amino acids. The extracellular domain of Porimin contains many 0-linked and seven N-linked glycosylation sites that define it as a new member of the mucin family. COS7 and 293 cells transiently transfected with Porimin cDNA were specifically recognized by anti-Porimin Ab in cell staining and immunoblotting experiments. When expressed in Jurkat cells, a His-tagged Porimin cDNA construct resulted in the generation of a specific 110-kDa-size protein that matched the molecular mass of the endogenous Porimin protein. Crosslinking of the Porimin receptor expressed on COS7 transfectants resulted in the loss of cell membrane integrity and cell death as measured by the leakage of intracellular lactate dehydrogenase. Both COS7 and 293 cells expressing transfected Porimin at a relatively high level lost their ability to adhere to culture dishes, suggesting a role for Porimin in cell adhesion. The Porimin gene was mapped to human chromosome 11q22.1 and is composed of four exons spanning 133 kb of genomic DNA.

PD-1 (programmed cell death-1) is the central inhibitory receptor regulating CD8 T cell exhaustion during chronic viral infection and cancer. Interestingly, PD-1 is also expressed transiently by activated CD8 T cells during acute viral infection, but the role of PD- 1 in modulating T cell effector differentiation and function is not well defined. To address this question, we examined the expression kinetics and role of PD-1 during acute lymphocytic choriomeningitis virus (LCMV) infection of mice. PD-1 was rapidly upregulated in vivo upon activation of naive virus-specific CD8 T cells within 24 h after LCMV infection and in less than 4 h after peptide injection, well before any cell division had occurred. This rapid PD- 1 expression by CD8 T cells was driven predominantly by antigen receptor signaling since infection with a LCMV strain with a mutation in the CD8 T cell epitope did not result in the increase of PD-1 on antigen-specific CD8 T cells. Blockade of the PD-1 pathway using anti-PD-L1 or anti-PD-1 antibodies during the early phase of acute LCMV infection increased mTOR signaling and granzyme B expression in virus-specific CD8 T cells and resulted in faster clearance of the infection. These results show that PD-1 plays an inhibitory role during the naive-to-effector CD8 T cell transition and that the PD-1 pathway can also be modulated at this stage of T cell differentiation. These findings have implications for developing therapeutic vaccination strategies in combination with PD-1 blockade. [ABSTRACT FROM AUTHOR]

Tubular cell necrosis is a key histological feature of acute kidney injury (AKI). Necroptosis is a type of programed necrosis, which is executed by mixed lineage kinase domain-like protein (MLKL) upon its binding to the plasma membrane. Emerging evidence indicates that necroptosis plays a critical role in the development of AKI. However, it is unclearwhether renal tubular cells undergo necroptosis in vivo and how the necroptotic pathway is regulated during AKI. Repulsive guidance molecule (RGM)-b is a member of the RGM family. Our previous study demonstrated that RGMb is highly expressed in kidney tubular epithelial cells, but its biological role in the kidney has not been well characterized. In the present study, we found that RGMb reduced membrane-associated MLKL levels and inhibited necroptosis in cultured cells. During ischemia/reperfusion injury (IRI) or oxalate nephropathy, MLKL was induced to express on the apical membrane of proximal tubular (PT) cells. Specific knockout of Rgmb in tubular cells (Rgmb cKO) increased MLKL expression at the apical membrane of PT cells and induced more tubular cell death and more severe renal dysfunction compared with wild-type mice. Treatment with the necroptosis inhibitor Necrostatin-1 or GSK'963 reduced MLKL expression on the apical membrane of PT cells and ameliorated renal function impairment after IRI in both wild-type and Rgmb cKO mice. Taken together, our results suggest that proximal tubular cell necroptosis plays an important role in AKI, and that RGMb protects against AKI by inhibiting MLKL membrane association and necroptosis in proximal tubular cells. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti–PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three treated animals without apparent hepatocellular injury. Viremia rebounded in the responder animal when antibody treatment was discontinued. Control of HCV replication was associated with restoration of intrahepatic CD4+ and CD8+ T-cell immunity against multiple HCV proteins. The responder animal had a history of broader T-cell immunity to multiple HCV proteins than the two chimpanzees that did not respond to PD-1 therapy. The results suggest that successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses. Anti–PD-1 immunotherapy may also facilitate control of other persistent viruses, notably the hepatitis B virus where options for long-term control of virus replication are limited. [ABSTRACT FROM AUTHOR]

CD4 T cells play a critical role in regulating CD8 T-cell responses during chronic viral infection. Several studies in animal models and humans have shown that the absence of CD4 T-cell help results in severe dysfunction of virus-specific CD8 T cells. However, whether function can be restored in already exhausted CD8 T cells by providing CD4 T-cell help at a later time remains unexplored. In this study, we used a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection to address this question. Adoptive transfer of LCMV-specific CD4 T cells into chronically infected mice restored proliferation and cytokine production by exhausted virus-specific CD8 T cells and reduced viral burden. Although the transferred CD4 T cells were able to enhance function in exhausted CD8 T cells, these CD4 T cells expressed high levels of the programmed cell death (PD)-1 inhibitory receptor. Blockade of the PD-1 pathway increased the ability of transferred LCMV-specific CD4 T cells to produce effector cytokines, improved rescue of exhausted CD8 T cells, and resulted in a striking reduction in viral load. These results suggest that CD4 T-cell immunotherapy alone or in conjunction with blockade of inhibitory receptors may be a promising approach for treating CD8 T-cell dysfunction in chronic infections and cancer. [ABSTRACT FROM AUTHOR]

Inhibitory receptors play a crucial role in regulating CD8 T-cell function during chronic viral infection. T-cell Ig- and mucin-domain- containing molecule-3 (Tim-3) is well known to negatively regulate T-cell responses, but its role in CD8 1-cell exhaustion during chronic infection in vivo remains unclear. In this study, we document coregulation of CD8 T cell exhaustion by Tim-3 and PD-i during chronic lymphocytic choriomeningitis virus infection. Whereas Tim-3 was only transiently expressed by CD8 T cells after acute infection, virus-specific CD8 T cells retained high Tim-3 expression throughout chronic infection. The majority (approximately 65% to 80%) of lym- phocytic choriomeningitis virus-specific CD8 T cells in lymphoid and nonlymphoid organs coexpressed Tim-3 and PD-i. This coexpression of Tim-3 and PD-i was associated with more severe CD8 1-cell exhaustion in terms of proliferation and secretion of effector cytokines such as lFN-'. TNF-a, and lL-2. Interestingly, CD8 T cells expressing both inhibitory receptors also produced the suppressive cytokine IL-b. Most importantly, combined blockade of Tim-3 and PD-i pathways in vivo synergistically improved CD8TceII responses and viral control in chronically infected mice. Taken together, our study defines a parameter for determining the severity of CD8 I cell dysfunction and for identifying virus-specific CD8 T cells that produce IL-b, and shows that targeting both PD-i and Tim-3 is an effective immune strategy for treating chronic viral infections. [ABSTRACT FROM AUTHOR]

The ability to induce durable transplantation tolerance predictably and consistently in the clinic is a highly desired but elusive goal. Progress is hampered by lack of appropriate experimental models in which to study resistance to transplantation tolerance: Here, we demonstrate that T helper 1-associated T box 21 transcription factor (Tbet) KO recipients exhibit allograft tolerance resistance specifically mediated by lL-17-producing CD8 T (T17) cells. Neutralization of IL-17 facilitates long-term cardiac allograft survival with combined T cell co-stimulation (CD28-CD80186 and CD154-CD4O) blockade in Tbet KO recipients. We have used this T17-biased Tbet KO model of allograft tolerance resistance to study the impact of targeting a T cell-co-stimulatory pathway, and demonstrate that targeting T cell Ig and mucin domain-1 (Tim-1) with anti-Tim-1 overcomes this resistance by specifically inhibiting the pathogenic IL-17-producing CD8 T17 cells. These data indicate that in the absence of Th1 immunity, CD8 T17 alloreactivity constitutes a barrier to transplantation tolerance. Targeting TIM-1 provides an approach to overcome resistance to tolerance in clinical transplantation. [ABSTRACT FROM AUTHOR]

Programmed death-i (PD-i) regulates T cell exhaustion during chronic infections. Blocking the PD-i:PD-ligand (PD-L) pathway reinvigorates exhausted CD8 T cells. Exactly how blocking PD-1:PD-L interactions improves T cell immunity, however, remains unclear. PD-1:PD-L blockade could reprogram all exhausted T cells to become antiviral effectors. Alternatively, this blockade might selectively expand a subset of exhausted T cells. We have identified two subpopulations of exhausted CD8 T cells during chronic viral infection in mice. One subset of exhausted CD8 T cells is rescued by αPD-L1 blockade, whereas the other subset appears more terminally differentiated and responds poorly to PD-1:PD-L blockade. Blocking PD-i:PD-L interactions reduces spontaneous apoptosis and enhances expansion and protective immunity of the rescuable subset, but not the more terminally differentiated subset of exhausted CD8 T cells. These results have implications for predicting clinical responses to PD-1-based therapeutic interventions and for understanding T cell dynamics during persisting infections. [ABSTRACT FROM AUTHOR]

The PD-1 costimulatory receptor inhibits T cell receptor signaling upon interacting with its ligands PD-L1 and PD-L2. The PD-1/PD-1 pathway is critical in maintaining self-tolerance. In this study, we examined the role of PD-1 in a mouse model of acute infection with Histoplasma capsulatum, a major human pathogenic fungus. In a lethal model of histoplasmosis, all PD-1-deficient mice survived infection, whereas the wild-type mice died with disseminated disease. PD-L expression on macrophages and splenocytes was up-regulated during infection, and macrophages from infected mice inhibited in vitro T cell activation. Of interest, antibody blocking of PD-1 significantly increased survival of lethally infected wild-type mice. Thus, our studies extend the role of the PD-1/PD-L pathway in regulating antimicrobial immunity to fungal pathogens. The results show that the PD-1/PD-1 pathway has a key role in the regulation of antifungal immunity, and suggest that manipulation of this pathway represents a strategy of immunotherapy for histoplasmosis. [ABSTRACT FROM AUTHOR]

An abstract of the article "Strength of PD-1 signaling differentially affects T-cell effector functions" by Fang Wei and colleagues is presented.

The article explains about programmed death-1 (PD-1). PD-1 is defined as a CD28 family member expressed on activated T cells, B cells and myeloid cells. Its structures are PD-1/L1 and PD-1/PD-L2 complexes. Both PD-1s are different because PD-1/L1 is broadly expressed on both professional and nonprofessional anti-presenting cells (APCs) as well as a wide variety of nonhematopoietic cell types, while PD-1/L2 is inducibly expressed on dendritic cells and macrophages.

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and CD8 + T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood-tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a "hot" tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.

PD-1 (programmed cell death-1) is the central inhibitory receptor regulating CD8 T cell exhaustion during chronic viral infection and cancer. Interestingly, PD-1 is also expressed transiently by activated CD8 T cells during acute viral infection, but the role of PD-1 in modulating T cell effector differentiation and function is not well defined. To address this question, we examined the expression kinetics and role of PD-1 during acute lymphocytic choriomeningitis virus (LCMV) infection of mice. PD-1 was rapidly up-regulated in vivo upon activation of naive virus-specific CD8 T cells within 24 h after LCMV infection and in less than 4 h after peptide injection, well before any cell division had occurred. This rapid PD-1 expression by CD8 T cells was driven predominantly by antigen receptor signaling since infection with a LCMV strain with a mutation in the CD8 T cell epitope did not result in the increase of PD-1 on antigen-specific CD8 T cells. Blockade of the PD-1 pathway using anti-PD-L1 or anti-PD-1 antibodies during the early phase of acute LCMV infection increased mTOR signaling and granzyme B expression in virus-specific CD8 T cells and resulted in faster clearance of the infection. These results show that PD-1 plays an inhibitory role during the naive-to-effector CD8 T cell transition and that the PD-1 pathway can also be modulated at this stage of T cell differentiation. These findings have implications for developing therapeutic vaccination strategies in combination with PD-1 blockade., Competing Interests: Conflict of interest statement: R.A. has patents on the PD-1 pathway and has served on the advisory board for Genentech/Roche and received research funding from Genentech and Merck. G.J.F. and A.H.S. have patents/pending royalties on the PD-1 pathway from Roche, Merck, Bristol-Myers Squibb, EMD Serono, Boehringer Ingelheim, AstraZeneca, Dako, and Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers Squibb, Xios, and Quiet. A.H.S. has served on advisory boards for Novartis, Surface Oncology, and Elstar. A.H.S. has received research funding from Novartis, Roche, UCB, Ipsen, and Quark. B.I.A. is an employee of Five Prime Therapeutics.

Tubular cell necrosis is a key histological feature of acute kidney injury (AKI). Necroptosis is a type of programed necrosis, which is executed by mixed lineage kinase domain-like protein (MLKL) upon its binding to the plasma membrane. Emerging evidence indicates that necroptosis plays a critical role in the development of AKI. However, it is unclear whether renal tubular cells undergo necroptosis in vivo and how the necroptotic pathway is regulated during AKI. Repulsive guidance molecule (RGM)-b is a member of the RGM family. Our previous study demonstrated that RGMb is highly expressed in kidney tubular epithelial cells, but its biological role in the kidney has not been well characterized. In the present study, we found that RGMb reduced membrane-associated MLKL levels and inhibited necroptosis in cultured cells. During ischemia/reperfusion injury (IRI) or oxalate nephropathy, MLKL was induced to express on the apical membrane of proximal tubular (PT) cells. Specific knockout of Rgmb in tubular cells (Rgmb cKO) increased MLKL expression at the apical membrane of PT cells and induced more tubular cell death and more severe renal dysfunction compared with wild-type mice. Treatment with the necroptosis inhibitor Necrostatin-1 or GSK'963 reduced MLKL expression on the apical membrane of PT cells and ameliorated renal function impairment after IRI in both wild-type and Rgmb cKO mice. Taken together, our results suggest that proximal tubular cell necroptosis plays an important role in AKI, and that RGMb protects against AKI by inhibiting MLKL membrane association and necroptosis in proximal tubular cells., Competing Interests: The authors declare no conflict of interest.

High surface expression of programmed death 1 (PD-1) is associated with T-cell exhaustion; however, the relationship between PD-1 expression and T-cell dysfunction has not been delineated. We developed a model to study PD-1 signaling in primary human T cells to study how PD-1 expression affected T-cell function. By determining the number of T-cell receptor/peptide-MHC complexes needed to initiate a Ca(2+) flux, we found that PD-1 ligation dramatically shifts the dose-response curve, making T cells much less sensitive to T-cell receptor-generated signals. Importantly, other T-cell functions were differentially sensitive to PD-1 expression. We observed that high levels of PD-1 expression were required to inhibit macrophage inflammatory protein 1 beta production, lower levels were required to block cytotoxicity and IFN-γ production, and very low levels of PD-1 expression could inhibit TNF-α and IL-2 production as well as T-cell expansion. These findings provide insight into the role of PD-1 expression in enforcing T-cell exhaustion and the therapeutic potential of PD-1 blockade.