The inhibitory receptor PD-1 differentially regulates effector and anergic autoreactive CD4 T cells during Type 1 Diabetes

University of Minnesota Ph.D. dissertation. July 2013. Major: Microbiology, Immunology and Cancer Biology. Advisor: Brian Fife, Ph.D. 1 computer file (PDF); xi, 207 188 pages.A variety of mechanisms act to prevent the inappropriate targeting of host tissues by the immune system, but these mechanisms can fail, leading to development of autoimmunity. Type 1 Diabetes is an autoimmune disease caused by T cell-mediated destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. This work focused on understanding islet-reactive CD4 T cells during Type 1 Diabetes progression by comparing T cell responses in diabetes-susceptible non-obese diabetic (NOD) mice to diabetes-resistant (B6.g7) mice. Our knowledge of how these cells are normally regulated and how that regulation breaks down leading to diabetes is limited due to a lack of reagents to track these cells in mice with normal T cell repertoires. The goal of this work was to develop models to study physiological numbers of islet-reactive CD4 T cells in mice in order to gain a better understanding of how these cells are regulated with an emphasis on one critical inhibitory pathway involving Programmed-Death 1 (PD-1). Using these models, we showed that in diabetes-susceptible NOD mice, the majority of islet-reactive CD4 T cells become activated, but the pathogenic subset capable of contributing to disease was relatively small. Rather, the majority of the population was adequately controlled by the host through induction of T cell anergy. In diabetes-resistant mice, islet-reactive CD4 T cells were present, but failed to become activated and subsequently did not infiltrate the pancreas. The inhibitory receptor PD-1 was important for suppressing CD4 T cell effector functions in NOD mice, including proliferation, trafficking to the pancreas, and localization within the pancreas. However, blockade of PD-1 did not promote CD4 T cell trafficking to the pancreas in diabetes-resistant mice. Unexpectedly, in NOD mice, PD-1 was predominantly involved in suppressing the functions of an activated effector population, not maintaining the anergic population. These findings provide new insight into the regulation of islet-reactive CD4 T cells, and show that PD-1 differentially contributes to the suppression of these cells