Negative Costimulation Research Articles

Expression of programmed cell death-1 and its ligand B7 homolog 1 in peripheral blood lymphocytes from patients with peripartum cardiomyopathy.

Immune response has been postulated to play a prominent role in the pathogenesis of peripartum cardiomyopathy (PPCM). Given the importance of programmed death (PD)-1 and its ligand B7 homologue 1 (B7-H1) costimulatory molecules as an immune regulatory pathway, this study aimed to investigate the effect of PD-1 and B7-H1 expression on immune response in peripheral blood lymphocytes from the patients with PPCM. PD-1 and B7-H1 may be involved in modulating immune response in PPCM. Peripheral blood lymphocytes were obtained from PPCM and pregnancy-matched healthy women. PD-1 and B7-H1 expression were determined using fluorescence quantitative reverse transcription-polymerase chain reactions (RT-PCR) and Western blot. The presence of serum interferon (IFN)-γ and interleukin (IL)-4 were determined with enzyme-linked immunosorbent assay. The levels of pro-brain natriuretic peptide and IFN-γ were markedly elevated, whereas the levels of left ventricular ejection fraction and IL-4 were significantly reduced in PPCM patients compared to controls. Additionally, both RT-PCR and Western blot revealed that the levels of PD-1 and B7-H1 expression were decreased significantly in PPCM patients compared with controls. A significant positive correlation was observed between PD-1 and B7-H1 expression. Furthermore, PD-1 and B7-H1 expression showed significant negative correlation with IFN-γ, as well as positive correlation with IL-4. Therefore, decreased expression of PD-1 and B7-H1 led to a dysregulating immune response such that cellular immunity linked to T helper (Th)1 cells was predominant over humoral immunity linked to Th2 cells in PPCM. This study provided the first findings that PD-1 and B7-H1 expression were decreased, which might impair functional regulation of negative costimulation on immune response that may work in the etiopathogenesis of PPCM.

Decreased expression of programmed death 1 on peripheral blood lymphocytes disrupts immune homeostasis in peripartum cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a disease of unknown pathogenesis. Programmed death 1 (PD1) has been postulated to modulate immune response through potential mechanisms that remain elusive. This study aimed to elaborate the expression and function of PD1 on peripheral blood lymphocytes (PBLs) in the development of PPCM. Specimens of PBLs were performed to determine the expression of PD1 mRNA using fluorescence quantitative RT-PCR, and Th cytokines by ELISA. Immune homeostasis was evaluated with T lymphocyte phenotypes and immunoglobulin (Ig) isotypes as well as complement factors (C). Morphology of lymphocytes was observed using transmission electronic microscope. Significantly elevated levels of interferon (IFN)-γ, percentages of CD3+, CD4+, CD8+ T lymphocytes, and pro-brain natriuretic peptide (BNP), but reduced levels of interleukin (IL)-4, IgG, IgM, IgA, C3, C4, and left ventricular ejection fraction (LVEF) were detected, which were associated with significantly lower of PD1 mRNA expression in PPCM relative to control. Furthermore, PD1 mRNA expression showed significant negative correlation with IFN-γ and CD3+, CD4+, CD8+ T lymphocytes, and proBNP as well as positive correlation with IL-4, IgG, IgM, IgA, C3, C4, and LVEF. The morphologic features of cells indicated that the PBLs in PPCM were in the state of activation. Therefore, decreased expression of PD1 mRNA led to LV dysfunction and functional dysregulation of negative costimulation on cellular immunity. This study provided the first findings that PD1 expression was decreased, which might disrupt immune homeostasis that enhanced cellular immunity was predominant over attenuated humoral immunity that may work in the etiopathogenesis of PPCM.

Characterization of a new lymphoid organs-specific endothelial cells subset with high expression of VISTA negative co-stimulator protein

Abstract Peripheral tolerance is regulated through a network of co-stimulatory and co-inhibitory ligands and receptors. Targeting these molecules or their pathways has been promising in clinic in both oncoimmunology and autoimmunity. V-set domain Ig Suppressor of T cell Activation (VISTA) is a recently identified co-inhibitory member of the B7 family. VISTA suppresses T cell immune responses; interference with its function results in susceptibility to autoimmunity. Investigating expression pattern of VISTA in various cell types and tissues in mice, we identified a sub-population of endothelial cells present only within secondary lymphoid organs, which express high levels of VISTA; a finding not previously reported. Characterization of this subset revealed that VISTA-expressing endothelial cells (VEECs) are predominantly of lymphatic endothelial cells (LECs) origin, however, only less than half of LECs in lymphoid organs are VEECs. As LECs have been shown to induce tolerance via co-inhibitory molecules such as PD-L1, we studied the role of VEECs in regard to immune tolerance. FACS-sorted VEECs cells from secondary lymphoid organs of NOD and DBA mice were evaluated for the expression levels of various peripheral tissue antigens associated with immune tolerance. Our results show that in NOD VEECs the AIRE transcription factor, as well as some diabetic autoimmunity-associated peripheral tissue antigens of pancreatic origin (insulin-2 and Rrad) are significantly up-regulated. To further investigate the regulatory role of VEECs, we applied co-culture assays and evaluated the effects of VISTA expression by endothelial cells on T cell function.

FcγRIIIa (CD16a) drives the differentiation of peripheral human naive CD4+ T-cells

Abstract Activated human naïve CD4+ T-cells express FcγRIIIa receptors, which may serve as a checkpoint for immune homeostasis. A positive co-stimulation from FcγRIIIa (CD16a) will override the negative co-stimulation to drive immune expansion in autoimmunity. In an autoimmune background, FcγRIIIa via pSyk signal generated IFN-γhigh, TH17 and TFH populations. FcγRIIIa-pSyk signal up-regulated more than 80-fold toll-like receptor (TLR)3 and TLR8 proteins and enzymes that drive epigenetic modifications. FcγRIIIa-pSyk was observed both upon in vitro activation of naïve CD4+ T-cells and in vivo in CD4+ gated cells in SLE patients. Activated CD4+ T-cells expressing CD25, CD69 and CD98 also show FcγRIIIa-pSyk signaling. Cells with FcγRIIIa-pSyk signaling show ICOS and Bcl6 expression, markers of TFH. Adaptor and TLR interacting proteins BTK, HMGB1, HRAS, and MyD88 were upregulated. Labeled ICs that bound to FcγRIIIa also co-localize with HMGB1 and MyD88 in activated CD4+ T-cells. Western blots of IPs generated with anti-FcγRIIIa antibody show association of HMGB1 and MyD88 with FcγRIIIa. Three enzymes from epigenetic array ATF2, HAT6, and KAT6A showed several folds increase from FcγRIIIa engagement by ICs vs. CD28 co-signal. Past literature from over three decades have suggested that CD4+ T-cells do not express Fc-receptors. Although, this may be true for quiescent normal CD4+ T-cells, activated CD4+ T-cells not only express FcγRIIIa but signal via Syk. FcγRIIIa mediated signal efficiently replaces CD28 co-signal and rescue naïve cells activated with sub-optimal CD3 ligation. FcγRIIIa will act as vehicle for DNA delivery to endosomes in T-cells. We describe a new role for FcγRIIIa in adaptive immunity mediated by CD4+ T-cell responses.

Loss of Peripheral Protection in Pancreatic Islets by Proteolysis-Driven Impairment of VTCN1 (B7-H4) Presentation Is Associated with the Development of Autoimmune Diabetes.

Ag-specific activation of T cells is an essential process in the control of effector immune responses. Defects in T cell activation, particularly in the costimulation step, have been associated with many autoimmune conditions, including type 1 diabetes (T1D). Recently, we demonstrated that the phenotype of impaired negative costimulation, due to reduced levels of V-set domain-containing T cell activation inhibitor 1 (VTCN1) protein on APCs, is shared between diabetes-susceptible NOD mice and human T1D patients. In this study, we show that a similar process takes place in the target organ, as both α and β cells within pancreatic islets gradually lose their VTCN1 protein during autoimmune diabetes development despite upregulation of the VTCN1 gene. Diminishment of functional islet cells' VTCN1 is caused by the active proteolysis by metalloproteinase N-arginine dibasic convertase 1 (NRD1) and leads to the significant induction of proliferation and cytokine production by diabetogenic T cells. Inhibition of NRD1 activity, alternatively, stabilizes VTCN1 and dulls the anti-islet T cell responses. Therefore, we suggest a general endogenous mechanism of defective VTCN1 negative costimulation, which affects both lymphoid and peripheral target tissues during T1D progression and results in aggressive anti-islet T cell responses. This mechanism is tied to upregulation of NRD1 expression and likely acts in two synergistic proteolytic modes: cell-intrinsic intracellular and cell-extrinsic systemic. Our results highlight an importance of VTCN1 stabilization on cell surfaces for the restoration of altered balance of immune control during T1D.

Acute and Chronic Rejection: Compartmentalization and Kinetics of Counterbalancing Signals in Cardiac Transplants

Acute and chronic rejection impact distinct compartments of cardiac allografts. Intramyocardial mononuclear cell infiltrates define acute rejection, whereas chronic rejection affects large arteries. Hearts transplanted from male to female C57BL/6 mice undergo acute rejection with interstitial infiltrates at 2 weeks that resolve by 6 weeks when large arteries develop arteriopathy. These processes are dependent on T cells because no infiltrates developed in T cell-deficient mice and transfer of CD4 T cells restored T cell as well as macrophage infiltrates and ultimately neointima formation. Markers of inflammatory macrophages were up-regulated in the interstitium acutely and decreased as markers of wound healing macrophages increased chronically. Programmed cell death protein, a negative costimulator, and its ligand PDL1 were up-regulated in the interstitium during resolution of acute rejection. Blocking PDL1:PD1 interactions in the acute phase increased interstitial T cell infiltrates. Toll-like receptor (TLR) 4 and its endogenous ligand hyaluronan were increased in arteries with neointimal expansion. Injection of hyaluronan fragments increased intragraft production of chemokines. Our data indicate that negative costimulatory pathways are critical for the resolution of acute interstitial infiltrates. In the arterial compartment recognition of endogenous ligands including hyaluronan by the innate TLRs may support the progression of arteriopathy.

Research progress of negative costimulator B7-H4 in urologic tumors

B7-H4 is a recently-identified member of B7 costimulation superfamily. B7-H4 serves as an inhibitory modulator of T cell response through suppressing the proliferation, activation, and cytokine production of T cells. B7-H4 is found to be abnormally expressed in multiple human tumors. Many studies have shown that B7-H4 expression is closely related to the progression and prognosis of urologic tumors. Investigation of B7-H4 function will provide new strategies for diagnosis and immunotherapy of urologic tumors. This article reviews the recent progress of B7-H4 research in urologic tumors.

Programmed Death-1 Shapes Memory Phenotype CD8 T Cell Subsets in a Cell-Intrinsic Manner

Memory phenotype T cells, found in unimmunized mice, display phenotypic and functional traits of memory cells and provide essential protection against infections, playing a role in both innate and adaptive immune responses. Mechanisms governing homeostasis of these memory phenotype T cells remain ill-defined. In this study, we reveal a crucial role of the negative costimulator programmed death-1 (PD-1) in regulating developmental fates of memory phenotype cells. Thus, in lymphoid organs and tissues of PD-1 knockout (KO) mice a marked accumulation of functional effector memory (T(EM)) phenotype CD8 T cells was observed. T(EM) phenotype cells from PD-1 KO mice exhibit decreased proliferation but increased survival potential. These cells could produce effector molecules constitutively, in response to phorbol esters or through bystander activation by innate stimuli. Similarly, in lymphopenia-induced proliferating CD8 T cells, whereby normally naive T cells acquire a memory phenotype, skewing toward a T(EM) phenotype was prominent in the absence of PD-1. Acquisition of the T(EM) phenotype was a CD8 T cell-intrinsic phenomenon as demonstrated by mixed bone marrow transfer experiments. Importantly, adoptively transferred PD-1 KO CD8 central memory T (T(CM)) cells converted into the T(EM) phenotype, indicating that PD-1 sets a major checkpoint in the T(CM) to T(EM) phenotype differentiation process. This was reflected by distinct patterns of gene expression of PD-1 KO T(CM) phenotype cells revealed by global transcriptional analysis. Additionally, adoptively transferred PD-1 KO T(EM) phenotype cells converted to a lesser degree to a T(CM) phenotype. Collectively, these data suggest that PD-1 shapes memory phenotype CD8 T cell subsets.

OP0197 CGEN-15001, A Novel Negative Co-Stimulator Fusion Protein is Effective in the Collagen-Induced Arthritis Mouse Model of Rheumatoid Arthritis

BackgroundCGEN-15001 is a fusion protein composed of the extracellular domain of CGEN-15001T fused to IgG Fc. CGEN-15001T was recently identified as a novel member of the B7/CD28 costimulatory family based...

The soluble isoform of CTLA‐4 as a regulator of T‐cell responses

CTLA-4 is a crucial immune regulator that mediates both negative costimulation signals to T cells, and regulatory T (Treg)-cell extrinsic control of effector responses. Here we present evidence supporting a novel mechanism for this extrinsic suppression, executed by the alternatively spliced soluble CTLA-4 isoform (sCTLA-4). Analyses of human T cells in vitro show that sCTLA-4 secretion can be increased during responses, and has potent inhibitory properties, since isoform-specific blockade of its activity significantly increased Ag-driven proliferation and cytokine (IFN-γ, IL-17) secretion. Treg cells were demonstrated to be a prominent source of sCTLA-4, which contributed to suppression in vitro when their numbers were limiting. The soluble isoform was also produced by, and inhibited, murine T cells responding to Ag in vitro, and blockade of its activity in vivo protected against metastatic spread of melanoma in mice. We conclude that sCTLA-4 is an important immune regulator, responsible for at least some of the inhibitory effects previously ascribed to the membrane-bound isoform. These results suggest that the immune system exploits the different CTLA-4 isoforms for either intrinsic or extrinsic regulation of T-cell activity.

Expression and biological function of programmed death ligands in human placenta mesenchymal stem cells

Mesenchymal stem cells (MSCs) play important roles in tissue regeneration due to their self-renewal, multilineage differentiation and immunosuppression abilities. MSCs can be isolated from various kinds of tissue, such as umbilical cord, cord blood and placenta. Human placenta mesenchymal stem cells (hPMSCs) possess stronger immunosuppressive properties, such as the ability to inhibit T-cell activation and proliferation, than human bone marrow MSCs. We have investigated that the roles of the programmed death ligands 1 and 2 (PDL1 and PDL2) in hPMSC adhesion, migration and immunosuppression were investigated. PDL1 and PDL2 were highly expressed by hPMSCs. Knockdown of PDL1 and/or PDL2 by siRNA increased hPMSC adhesion, but greatly decreasing migration. PDL1 and PDL2 expressed on hPMSCs inhibited T-cell proliferation by arresting the cell cycle. Knockdown of PDL1 and/or PDL2 in hPMSCs, however, had no effect on the expression of CD69, a T-cell early activation marker found on both CD4(+) and CD8(+) T-cell subsets. In summary, the roles of the negative co-stimulators PDL1 and PDL2 is on the adhesion, migration and immunosuppression of hPMSCs. These findings may be useful regarding the potential use of hPMSCs in clinical cell.

PD-L1/PD-1 Co-Stimulation, a Brake for T cell Activation and a T cell Differentiation Signal.

For T cell activation, three signals have to be provided from the antigen presenting cell; Signal 1 (antigen recognition), signal 2 (co-stimulation) and signal 3 (cytokine priming). Blocking negative co-stimulation during antigen presentation to T cells is becoming a promising therapeutic strategy to enhance cancer immunotherapy. Here we will focus on interference with PD-1/PD-L1 negative co-stimulation during antigen presentation to T cells as a therapeutic approach. We will discuss the potential mechanisms and the therapeutic consequences by which interference/inhibition with this interaction results in anti-tumour immunity. Particularly, we will comment on whether blocking negative co-stimulation provides differentiation signals to T cells undergoing antigen presentation. A major dogma in immunology states that T cell differentiation signals are given by cytokines and chemokines (signal 3) rather than co-stimulation (signal 2). We will discuss whether this is the case when blocking PD-L1/PD-1 negative co-stimulation.

Different roles of PD-L1 and FasL in immunomodulation mediated by human placenta-derived mesenchymal stem cells

Mesenchymal stem cells (MSCs) derived from either bone marrow (BMSCs) or placenta (PMSCs) have the capacity to suppress immune responses to mitogenic and allogeneic stimulations. Both cell contact and soluble factor dependent mechanisms have been proposed to explain this immunosuppression. This study explored the roles of some of cell surface molecules expressed on human PMSCs (hPMSCs) in hPMSC mediated immunomodulation. hPMSCs strongly suppressed mitogen and allogeneic peripheral mononuclear cells (PBMCs) induced T cell activation and proliferation. hPMSCs constituently expressed programmed death-ligand 1 (PD-L1) and Fas ligand (FasL) molecules. Neutralising antibodies to-PD-L1 and FasL significantly reduced the suppressive effect of hPMSCs on T cell proliferation. However, only anti-PD-L1 antibody partially restored early T cell activation suppressed by hPMSCs. Anti-FasL antibody but not anti-PD-L1 antibody reduced apoptosis of activated T cell indicating that FasL molecule plays a role in inducing apoptosis of activated T cells, although overall hPMSCs diminished T cell apoptosis. Different effects of PD-L1 and FasL molecules on T cell activation and activated T cell apoptosis suggest that these two molecules influence T cell response at different stages. hPMSCs significantly prevented activated T cells from going into S phase. Both antibodies to PD-L1 and FasL had significant effect on reversing the effect of hPMSCs on cell cycles. hPMSCs reduced INF-γ but increased IL-10 production by mitogen activated T cells. Both antibodies partially abolished the effect of hPMSCs on INF-γ and IL-10 production. These data demonstrated that PD-L1 and FasL molecules play significant roles in immunomodulation mediated by hPMSCs. This study provides a rational basis for modulation of negative costimulators on hPMSCs to increase their immunosuppressive properties in their therapeutic applications.

Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined. Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8(+) T cells in the infusion product, a more differentiated effector phenotype of the CD8(+) population, and a higher frequency of CD8(+) T cells coexpressing the negative costimulation molecule "B- and T-lymphocyte attenuator" (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified. These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8(+) T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.

MODULATING CO-STIMULATION DURING ANTIGEN PRESENTATION TO ENHANCE CANCER IMMUNOTHERAPY.

One of the key roles of the immune system is the identification of potentially dangerous pathogens or tumour cells, and raising a wide range of mechanisms to eliminate them from the organism. One of these mechanisms is activation and expansion of antigen-specific cytotoxic T cells, after recognition of antigenic peptides on the surface of antigen presenting cells such as dendritic cells (DCs). However, DCs also process and present autoantigens. Therefore, antigen presentation has to occur in the appropriate context to either trigger immune responses or establishing immunological tolerance. This is achieved by co-stimulation of T cells during antigen presentation. Co-stimulation consists on the simultaneous binding of ligand-receptor molecules at the immunological synapse which will determine the type and extent of T cell responses. In addition, the type of cytokines/chemokines present during antigen presentation will influence the polarisation of T cell responses, whether they lead to tolerance, antibody responses or cytotoxicity. In this review, we will focus on approaches manipulating co-stimulation during antigen presentation, and the role of cytokine stimulation on effective T cell responses. More specifically, we will address the experimental strategies to interfere with negative co-stimulation such as that mediated by PD-L1 (Programmed cell death 1 ligand 1)/PD-1 (Programmed death 1) to enhance anti-tumour immunity.

Abstract PL03-02: Current status of recombinant pox-viral vaccines

Abstract PL03-02: Current status of recombinant pox-viral vaccines

Aberrant expression of the negative costimulator PD-1 on T cells in granulomatosis with polyangiitis

Persistent T-cell activation is frequently observed in granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis). T-cell activation is usually balanced by negative costimulatory molecules. The negative costimulator programmed death receptor-1 (PD-1) and its relevance to T-cell immunity have not been studied so far in GPA. Thus it is the aim of the study to characterize the role of PD-1 in GPA. Thirty-two patients suffering from GPA and 19 age-matched healthy controls (HCs) were enrolled. T-lymphocyte subsets from peripheral blood were analysed by flow cytometry for the expression of PD-1. The frequency of memory T cells and T cells producing pro-inflammatory cytokines was determined. Renal biopsies from GPA patients were stained for CD3 and PD-1. PD-1 expression was increased on T-helper cells (Th cells) from GPA patients as compared with HCs. In addition, parameters of persistent T-cell activation and production of pro-inflammatory cytokines were positively associated with numbers of PD-1(+) Th cells in patients but not in HCs. Latent infection with CMV seemed to enhance PD-1 expression on CD4(+) and CD4(+)CD25(-) T cells. Interestingly, expression of PD-1 on CD4(+)CD25(+)T cells was inversely correlated with relapse rate. Importantly, lesional T cells were mostly lacking PD-1. The expression of the negative costimulator PD-1 is altered in GPA and might counterbalance persistent T-cell activation.

PD-1 Blockade Augments Th1 and Th17 and Suppresses Th2 Responses in Peripheral Blood From Patients With Prostate and Advanced Melanoma Cancer

Negative costimulation on T cells is exploited by both prostate cancer and melanoma to evade antitumor immunity. Blocking such mechanisms restores antitumor immunity as was demonstrated by the improved survival of patients with metastatic melanoma after treatment with an antibody blocking the CTLA-4 inhibitory receptor (ipilimumab). Enhanced expression of another inhibitory immunoreceptor, programmed death-1 (PD-1), and its ligand, PD-L1, was found to correlate with a poor prognosis in prostate cancer and melanoma. PD-1-blocking antibodies are being developed to modulate antitumor immune responses. To support preclinical and clinical development of anti-PD-1 therapy, we sought to develop biomarker assays that can detect the effect of PD-1-blocking agents in whole blood and peripheral blood mononuclear cells. In this study, we assessed the effect of PD-1 blockade in modulating super antigen (staphylococcus enterotoxin B)-induced and recall antigen (tetanus toxoid)-induced T-cell reactivity in vitro using whole blood and peripheral blood mononuclear cells from patients with advanced melanoma, prostate cancer, and healthy controls. PD-1 blockade was found to shift antigen-induced cellular reactivity toward a proinflammatory Th1/Th17 response, as evidenced by enhanced production of interferon γ, interleukin (IL)-2, tumor necrosis factor α, IL-6, and IL-17 and reduced production of the Th2 cytokines IL-5 and IL-13. It is interesting to note that suppression of Th2 responsivity was seen with whole blood cells only from patients with cancer. Taken together, we identified novel biomarker assays that might be used to determine the functional consequences of PD-1 blockade in peripheral blood cells from patients with cancer. How these assays translate to the local antitumor response remains to be established in a clinical setting.

The Role of Coinhibitory Signaling Pathways in Transplantation and Tolerance

Negative costimulatory molecules, acting through so-called inhibitory pathways, play a crucial role in the control of T cell responses. This negative “second signal” opposes T cell receptor activation and leads to downregulation of T cell proliferation and promotes antigen specific tolerance. Much interest has focused upon these pathways in recent years as a method to control detrimental alloresponses and promote allograft tolerance. However, recent experimental data highlights the complexity of negative costimulatory pathways in alloimmunity. Varying effects are observed from molecules expressed on donor and recipient tissues and also depending upon the activation status of immune cells involved. There appears to be significant overlap and redundancy within these systems, rendering this a challenging area to understand and exploit therapeutically. In this article, we will review the literature at the current time regarding the major negative costimulation pathways including CTLA-4:B7, PD-1:PD-L1/PD-L2 and PD-L1:B7-1, B7-H3, B7-H4, HVEM:BTLA/CD160, and TIM-3:Galectin-9. We aim to outline the role of these pathways in alloimmunity and discuss their potential applications for tolerance induction in transplantation.

Intrinsic and extrinsic control of peripheral T‐cell tolerance by costimulatory molecules of the CD28/ B7 family

Positive and negative costimulation by members of the CD28 family is critical for the development of productive immune responses against foreign pathogens and their proper termination to prevent inflammation-induced tissue damage. In addition, costimulatory signals are critical for the establishment and maintenance of peripheral tolerance. This paradigm has been established in many animal models and has led to the development of immunotherapies targeting costimulation pathways for the treatment of cancer, autoimmune disease, and allograft rejection. During the last decade, the complexity of the biology of costimulatory pathways has greatly increased due to the realization that costimulation does not affect only effector T cells but also influences regulatory T cells and antigen-presenting cells. Thus, costimulation controls T-cell tolerance through both intrinsic and extrinsic pathways. In this review, we discuss the influence of costimulation on intrinsic and extrinsic pathways of peripheral tolerance, with emphasis on members of the CD28 family, CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4), and programmed death-1 (PD-1), as well as the downstream cytokine interleukin-1 (IL-2).