T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) results from destruction of pancreatic beta cells by T cells of the immune system. Despite improvements in insulin analogs and continuous blood glucose level monitoring, there is no cure for T1D, and some individuals develop life-threatening complications. Pancreas and islet transplantation have been attractive therapeutic approaches; however, transplants containing insulin-producing cells are vulnerable to both recurrent autoimmunity and conventional allograft rejection. Current immune suppression treatments subdue the immune system, but not without complications. Ideally a successful approach would target only the destructive immune cells and leave the remaining immune system intact to fight foreign pathogens. This review discusses the autoimmune diabetes disease process, diabetic complications that warrant a transplant, and alloimmunity. First, we describe the current understanding of autoimmune destruction of beta cells including the roles of CD4 and CD8 T cells and several possibilities for antigen-specific tolerance induction. Second, we outline diabetic complications necessitating beta cell replacement. Third, we discuss transplant recognition, potential sources for beta cell replacement, and tolerance-promoting therapies under development. We hypothesize that a better understanding of autoreactive T cell targets during disease pathogenesis and alloimmunity following transplant destruction could enhance attempts to re-establish tolerance to beta cells.

Keywords: T cells; alloimmunity; autoimmune diseases; immunology; tolerance induction; transplantation immunology; type 1 diabetes.

Figure 1

Type 1 diabetes pathogenesis and potential therapeutic avenues. Type 1 diabetes arises due to failure of several key checkpoints. Defective central tolerance (1 and 2) allows islet-reactive CD4 and CD8 T cells to escape the thymus as naive cells and reach the pancreatic lymph node. In the pancreatic lymph node, autoreactive CD4 T cells interact with dendritic cells presenting islet antigen (3) and can become T helper 1 (T_H1), T_FH, pTreg, or anergic cells. T_FH cells help B cells produce high affinity islet-specific antibodies (4). T_H1 cells activate dendritic cells and enhance antigen presentation to islet-specific CD8 T cells (5) to induce effector CD8 T cell skewing (6). T_H1 cells traffic to the pancreas (7), secrete pro-inflammatory cytokines interferon gamma (IFNγ) and TNFα, and induce beta cell death (8). T_H1-derived IFNγ and TNFα stimulate M1 macrophages in the islets to produce ROS, TNFα, and IL-1β (9), which in turn amplify beta cell death cycle (10). Resulting inflammation leads to increased CD8 T cell infiltration and direct beta cell killing via perforin and granzyme B (11) and attempts by nTregs and pTregs to dampen this response via TGFβ and IL-10 (12). Potential therapeutic strategies include (A) infusion of ex vivo expanded (broadly reactive or pancreas-specific) Tregs, (B) re-educating T_H1 cells through approaches like peptide-linked apoptotic splenocytes, and (C) promoting beta cell-intrinsic expression of defense molecules in situ or engineering transplanted beta cells to be more resistant to T cell-mediated attack.