Effect of hyperglycemia on effector and regulatory CD4 T cells in NOD mice

Type 1 diabetes (T1D) is a direct consequence of a failure in immune tolerance to islet autoantigens in both humans and nonobese diabetic (NOD) mice. It is characterized by hyperglycemia and vascular complications arising from suboptimal control of blood level. It has been shown that acute hyperglycemia can initially induce an immunosuppression followed by homeostatic proliferation of T cells and that in chronic hyperglycemia initiation of adaptive immunity is impaired (1, 2). Unfortunately a link between hyperglycemia and suppressed (induced) adaptive responses has received little attention. Due to high diversity of TCRs on T lymphocytes, it is very difficult to monitor in vivo dynamics of effector or regulatory T cells on per cell basis. To study the role of hyperglycemia on diversity and specificity of different subsets of CD4+ T cells, we have made mice that possess a mini-repertoire of áâTCRs (TCRmini) on NOD background (NODmini). In this model TCRmini repertoire can be comprehensively monitored at the level of a single T cell clone, as we recently characterized similar repertoire in non-autoimmune prone C57BL/6 mice (3, 4). Our NODmini mice have polyclonal yet limited repertoire of T cells, do not develop spontaneous diabetes, and are perfectly suitable to monitor influence of induced hyperglycemia on clonal expansion of T cell compartment without previous diabetes. Immune based therapies are focused on influencing the balance between autoreactive and regulatory T cells either by suppressing former or inducing latter cells, often using immunosuppressive drugs. As acute hyperglycemia induces temporal lymphopenia, and homeostatic peripheral expansion has different effect on effector versus regulatory compartment, hyperglycemic stress will tip the balance between these subsets of T cells and will influence course of action during immunotherapeutic interventions. To determine effect of hyperglycemia on effector and regulatory CD4 T cells in mice with diabetes prone genetic background and to understand the consequences this process on rejection/acceptance of allogeneic islet transplants we propose to 1) Asses the effect of hyperglycemia on diversity and specificity of regulatory and effector T cells in diabetes prone environment and 2) to determine spatial and temporal effect of hyperglycemia on allospecific T cells during response to allogeneic islets transplantation.