Co-stimulate or Co-inhibit Regulatory T Cells,Which Side to Go?

ABSTRACT

Co-stimulatory and co-inhibitory molecules direct the “second signal,” which largely determines the outcome of the “first signal” generated by the interaction of T cell receptor (TCR) with cognate MHC–peptide complex. The co-stimulatory and co-inhibitory signals are key mechanistic contributors to the regulation of adaptive immunity, especially the T cell–mediated immune response. Regulatory T cells (Tregs) are a special population of T cells, which unlike other T cells function as “attenuators” to suppress T cell immunity. Dysregulation of either the “second signal” or Tregs leads to an unbalanced immune system, which can result in a range of immune-related disorders, including autoimmune diseases, chronic infections, and tumors. In contrast, precise manipulation of these two systems offers tremendous clinical opportunities to treat these same diseases. Co-stimulatory and co-inhibitory molecules modulate immunity at molecular level, whereas Tregs delicately control the immune response at cellular level. Accumulating evidence has demonstrated that these two regulatory strategies converge and synergize with each other. This review discusses recent progress on the roles of co-stimulatory and co-inhibitory signals in the context of Tregs.     

Targeting lymphocyte co-stimulation: From bench to bedside

T and B lymphocytes are central regulators and effectors of immune responses and are believed to have a key role in many autoimmune diseases. Targeting the activation or effector function of lymphocytes is a potentially effective approach to treat autoimmunity. Typically, T-cell activation occurs after engagement of the T-cell receptor with its cognate peptide-major histocompatibility complex (signal 1) and subsequent engagement of co-stimulatory molecules (signal 2). This “second signal” contributes to T-cell activation by promoting proliferation, survival, and effector function. In general, activation in the absence of co-stimulation leads to a reduced immune response, anergy, or even tolerance. B-cell activation similarly requires co-stimulation for the development of complete effector function. The most potent co-stimulatory molecules identified to date are CD28 for T-cells and CD40 for B-cells. Both molecules are recognized for their potential as immune modulators; however, thus far neither molecule has been successfully targeted directly for the treatment of autoimmune disease. The only current therapy to target either of these pathways is cytotoxic T-lymphocyte antigen-4 (CTLA-4-Ig), which indirectly blocks CD28 signaling and has proven efficacy in rheumatoid arthritis and juvenile idiopathic arthritis patients. In addition to CD28 and CD40, an array of other co-stimulatory as well as inhibitory pathways has recently been identified and scientists are just beginning to understand how these different signaling pathways interact to regulate lymphocyte activation. In the more than two decades since the discovery of the first co-stimulatory molecule, the full clinical potential of these pathways is yet to be realized. In this review, we will primarily focus on CD28 and CD40 which are the most clinically validated co-stimulatory pathways, and briefly summarize and discuss some of the other T-cell co-stimulatory molecules.     

The role of B7-2 (CD86) in tumour immunity

Tumour cells engineered to express co-stimulatory molecules on their surface provide researchers with powerful new tools to manipulate antitumour responses. It has been demonstrated that B7-1+ and B7-2+ tumour cells can elicit effective responses against their wild-type counterparts. This response is primarily mediated by CD8+ cytolytic T-lymphocytes. The co-stimulatory ability of B7-2+ tumour cells is comparable to that of B7-1+ tumour cells, though with some exceptions. However, on host antigen-presenting cells (APC), B7-2 plays a dominant role in inducing T-cell-mediated immune responses. Up-regulation of B7-2 on host APC may, therefore, present an effective means of generating potent antitumour immunity.     

Belatacept prophylaxis against organ rejection in adult kidney-transplant recipients

End-stage renal disease is a major health problem worldwide, with kidney transplantation being the treatment of choice. Calcineurin inhibitors are still the cornerstone of immunosuppressive therapy. However, they have well-known nephrotoxic affects and increase the risk of cardiovascular disease and cancer. In contrast, belatacept is a biological immunosuppressive agent that inhibits the T-cell co-stimulation. It is approved by the US Food and Drug Administration and the European Medicine Agency for use in adult kidney-transplant recipients to prevent acute rejection. Developmental studies show that belatacept is as efficient as calcineurin inhibitors at preventing acute rejection. In addition, kidney function is better and cardiovascular risk factors are reduced in patients given belatacept. Herein, the authors review the published evidence concerning the efficacy and safety of belatacept and discuss its potential specific indications.     

Hsp60-mediated T cell stimulation is independent of TLR4 and IL-12

Heat shock protein (Hsp) 60 is thought to function as endogenous danger signal by activating professional antigen-presenting cells (APC) through toll-like receptor (TLR) 4 and CD14, a mechanism that is also used by bacterial LPS. We recently showed that Hsp60 binds LPS and enhances LPS-induced immune stimulation. On the other hand, we also observed immune stimulation by Hsp60 independent of LPS which was partially mediated by Hsp60-induced IFN alpha. Here, we study the mechanisms involved in immune stimulation mediated by endotoxin-free Hsp60. We show that T cell co-stimulation induced by LPS-free Hsp60 was independent of TLR4 and the TLR-associated myeloide differentiation factor 88-signaling pathway. LPS-free Hsp60 did not induce IL-6, IL-12 or tumor necrosis factor alpha production in APC nor were these cytokines needed for Hsp60-mediated T cell co-stimulation in the absence of LPS. In contrast to endotoxin-free Hsp60, T cell co-stimulation induced by LPS or Hsp60/LPS complexes strictly depended on IL-12 and functional TLR-4. Furthermore, we show that LPS-free Hsp60 enhances IFN alpha expression in APC and that this cytokine represents one important mediator in immune stimulation by Hsp60 in the absence of LPS. Taken together, we provide evidence that endotoxin-free Hsp60 and LPS or Hsp60/LPS complexes employ different signaling mechanisms to transduce co-stimulatory signals.     

Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs

Negative co-stimulatory signaling mediated via cell surface programmed death (PD)-1 expression modulates T and B cell activation and is involved in maintaining peripheral tolerance. In this study, we examined the effects of a fully human PD-1-abrogating antibody on the in vitro expansion and function of human vaccine-induced CD8+ T cells (CTLs) specific for the melanoma-associated antigens glycoprotein 100 (gp100) and melanoma antigen recognized by T cells (MART)-1. PD-1 blockade during peptide stimulation augmented the absolute numbers of CD3+, CD4+, CD8+ and gp100/MART-1 MHC:peptide tetramer+ CTLs. This correlated with increased frequencies of IFN-gamma-secreting antigen-specific cells and augmented lysis of gp100+/MART-1+ melanoma targets. PD-1 blockade also increased the fraction of antigen-specific CTLs that recognized melanoma targets by degranulation, suggesting increased recognition efficiency for cognate peptide. The increased frequencies and absolute numbers of antigen-specific CTLs by PD-1 blockade resulted from augmented proliferation, not decreased apoptosis. Kinetic analysis of cytokine secretion demonstrated that PD-1 blockade increased both type-1 and type-2 cytokine accumulation in culture without any apparent skewing of the cytokine repertoire. These findings have implications for developing new cancer immunotherapy strategies.     

LIGHT is dispensable for CD4+ and CD8+ T cell and antibody responses to influenza A virus in mice

The tumor necrosis factor family ligands, LIGHT (lymphotoxin like, exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes), 4-1BBL and CD70, are found in the same gene cluster on mouse chromosome 17. Although the roles of 4-1BB-4-1BBL and CD27-CD70 interactions in anti-viral T cell responses have been well established, the role of LIGHT in T cell activation/expansion in vivo is less clear. Under conditions that were previously employed to demonstrate a role for 4-1BBL in CD8+ T cell memory, wild-type and LIGHT-/- mice were infected with influenza A virus and primary and memory/recall responses were measured at various time points thereafter. Neither primary expansion nor memory/recall CD8+ T cell responses were affected by the absence of LIGHT, as measured up to 2 months post-infection. CD4+ T cell responses were also unaffected by LIGHT deficiency. Furthermore, we found that LIGHT played no role in the induction of influenza-specific IgG1 and IgG2a serum antibodies. Taken together, these data suggest that LIGHT is dispensable for the acquired immune response to influenza virus in mice with no effect on the induction, maintenance or reactivation of CD8+ T cell memory.     

Homotypic interaction of the heat-stable antigen is not responsible for its co-stimulatory activity for T cell clonal expansion

The heat-stable antigen (HSA) is an important co-stimulatory molecule on antigen-presenting cells (APC). However, the receptor on T cells that receives the co-stimulatory signal from HSA has not been identified. Because the HSA is transiently expressed on T cells after the T cell receptor/CD3 complex is engaged, and because it can bind to itself in a homotypic fashion, it has been proposed that homotypic interaction of HSA is responsible for its co-stimulatory activity. Here we test this hypothesis using mice that have a targeted mutation of the HSA gene, as well as novel transgenic mice that constitutively express HSA on T cells. We show that HSA-deficient T cells remain responsive to co-stimulation by HSA. Furthermore, constitutive expression of HSA does not enhance T cell response to co-stimulatory by HSA. Taken together, our results demonstrate that homotypic interaction of HSA is not responsible for co-stimulation mediated by HSA expressed on APC.     

器官移植免疫耐受的研究进展

综述器官移植免疫耐受研究方面的最新进展，重点阐述诱导和维持免疫耐受的机制和方法。介绍一些具体方案，包括建立异基因骨髓嵌合体，阻断T细胞活化第二信号和转基因技术诱导移植免疫耐受。并对临床免疫耐受的前景和现实问题进行了客观的评价。     

Co-stimulatory blockade with belatacept in kidney transplantation

Calcineurin inhibitors (CNIs) are the cornerstone of immunosuppression after transplantation but can exert negative effects on chronic allograft function and metabolic profile. Belatacept, a selective co-stimulation blocker of T cells, is the first biologic agent approved for maintenance immunosuppression in kidney transplantation. Studies reveal better preservation of glomerular filtration rate and improved metabolic end points with belatacept when compared to CNIs. Increased incidence of acute rejection is noted with belatacept but overall graft survival looked similar at 5 years. Risk for posttransplant lymphoproliferative disorder is higher in Epstein–Barr virus-seronegative recipients of belatacept. Belatacept seems to be a promising drug, and further experience with its use will define its future role.