Opposing Effects of CTLA4 Insufficiency on Regulatory versus Conventional T Cells in Autoimmunity Converge on Effector Memory in Target Tissue

Quantitative variations in CTLA4 expression, because of genetic polymorphisms, are associated with various human autoimmune conditions, including type 1 diabetes (T1D). Extensive studies have demonstrated that CTLA4 is not only essential for the suppressive role of regulatory T cells (T-reg) but also required for intrinsic control of conventional T (T-conv) cells. We report that a modest insufficiency of CTLA4 in mice, which mimics the effect of some human CTLA4 genetic polymorphisms, accompanied by a T1D-permissive MHC locus, was sufficient to induce juvenile-onset diabetes on an otherwise T1D-resistant genetic background. Reduction in CTLA4 levels had an unanticipated effect in promoting T-reg function both in vivo and in vitro. It led to an increase in T-reg memory in both lymphoid and nonlymphoid target tissue. Conversely, modulating CTLA4 by either RNA interference or Ab blockade promoted conventional effector memory T cell formation in the T-conv compartment. The CD4(+) conventional effector memory T cells, including those within target tissue, produced IL-17 or IFN-gamma. Blocking IL-7 signaling reduced the Th17 autoimmune compartment but did not suppress the T1D induced by CTLA4 insufficiency. Enhanced effector memory formation in both T-conv and T-reg lineages may underpin the apparently dichotomized impact of CTLA4 insufficiency on autoimmune pathogenesis. Therefore, although the presence of CTLA4 plays a critical role in controlling homeostasis of T cells, its quantitative variation may impose diverse or even opposing effects on distinct lineages of T cells, an optimal sum of which is necessary for preservation of T cell immunity while suppressing tissue damage.