Coinhibitory T-Cell Signaling in Islet Allograft Rejection and Tolerance

Abstract

Autoaggressive T cells directed against insulin secreting pancreatic β-cells mediate the development of type 1 diabetes. Islet transplantation offers superior glycemic control over exogenous insulin, but chronic immunosuppression limits its broad application. Pathogenic T cells are also important in allograft rejection. Inducing and maintaining antigen-specific peripheral T-cell tolerance toward β-cells is an attractive strategy to prevent autoimmune disease, and to facilitate treatment of diabetes with islet allografts without long-term immunosuppression. Recent efforts have focused on blocking costimulatory T-cell signals for tolerance induction. Although costimulatory blockade can prolong graft survival, true immunological tolerance remains elusive. Costimulatory signals may even be required for the maintenance of peripheral tolerance. The discovery of novel coinhibitory T-cell pathways, including CTLA-4, PD-1, and BTLA, offers an alternative approach. Stimulating negative T cell cosignals alone or in combination may help induce tolerance. The focus of this review is to summarize the strategies directed at turning off the immune response by exploiting these negative cosignaling pathways in tolerance induction in islet transplantation. Activating several coinhibitory pathways together may be synergistic in preventing pathogenic T-cell responses. Tolerance induction will likely rely on understanding the balance of positive and negative signals affecting the state of T-cell activation.

Combined Coinhibitory and Costimulatory Modulation with Anti-BTLA and CTLA4Ig Facilitates Tolerance in Murine Islet Allografts

“…The emerging importance of negative cosignaling molecules, including CTLA-4/CD152 (14), programmed cell death-1 (PD-1/CD279) (15) and B and T lymphocyte attenuator (BTLA/CD272) (16), adds an additional dimension to the complexity in which T lymphocytes are regulated (17). Programmed cell death ligand-1 immunoglobulin (PDL1Ig) targeting the PD-1 coinhibitory pathway has been used successfully to enhance anti-CD40L (CD154) induced islet allograft survival (18), and to prolong cardiac allografts in CD28-deficient recipients (19).…”

Immune Tolerance Induction by Integrating Innate and Adaptive Immune Regulators

“…Some members of the co-stimulatory family negatively regulate T cell responses and are called co-inhibitors. An unbalanced presentation of co-inhibitory signals by DCs could also lead to suppression of adverse immune responses such as that in transplant rejection (124). Thus, DCs uploaded with specific antigens can be manipulated to be immunogenic to fight cancer and infectious agents, or tolerogenic to specifically turn off transplant immunity and autoimmunity (43,80,112).…”

The MHC-Based Suppression (MBS) Theory: Implications for Transplantation

“…Naive T cells tend to respond to inhibitory signaling by becoming anergic, and this is reversible [17] whilst armed effector cells respond to the same stimuli by either apoptosis or, if they survive, then become active regulatory cells, able to inhibit a new influx of primed antigen-specific cells; this state is not reversible [17]. The concept of co-inhibition was introduced more than 10 years ago [24,25], and has slowly expanded . The term now includes signaling via CD152-mediated inhibition of CD28, by competitive binding of CD80/CD86, signaling via PD1/PD1 ligand, and production of inhibitory cytokines, such as IL 10 and TGF-beta.…”