CTLA-4 is required by CD4+CD25+ Treg to control CD4+ T-cell lymphopenia-induced proliferation

CTLA-4 is constitutively expressed by CD4(+)CD25(+)Foxp3(+) Treg but its precise role in Treg function is not clear. Although blockade of CTLA-4 interferes with Treg function, studies using CTLA-4-deficient Treg have failed to reveal an essential requirement for CTLA-4 in Treg suppression in vivo. Conditional deletion of CTLA-4 in Foxp3(+) T cells disrupts immune homeostasis in vivo but the immune processes disrupted by CTLA-4 deletion have not been determined. We demonstrate that Treg expression of CTLA-4 is essential for Treg control of lymphopenia-induced CD4 T-cell expansion. Despite IL-10 expression, CTLA-4-deficient Treg were unable to control the expansion of CD4(+) target cells in a lymphopenic environment. Moreover, unlike their WT counterparts, CTLA-4-deficient Treg failed to inhibit cytokine production associated with homeostatic expansion and were unable to prevent colitis. Thus, while Treg developing in the absence of CTLA-4 appear to acquire some compensatory suppressive mechanisms in vitro, we identify a non-redundant role for CTLA-4 in Treg function in vivo.