CTLA-4 regulates the requirement for cytokine-induced signals in T H 2 lineage commitment

The relative importance of the cytokine milieu versus cytolytic T lymphocyte-associated antigen 4 (CTLA-4) and T cell receptor signal strength on T cell differentiation remains unclear. Here we have generated mice deficient for signal transducer and activator of transcription 6 (STAT6) and CTLA-4 to determine the role of CTLA-4 in cytokine-driven T cell differentiation. CTLA-4−deficient T cells bypass the need for STAT6 in the differentiation of T helper type 2 (TH2) cells. TH2 differentiation of cells deficient for both STAT6 and CTLA-4 is accompanied by induction of GATA-3 and the migration of TH2 cells to peripheral tissues. CTLA-4 deficiency also affects the balance of the nuclear factors NFATc1 and NFATc2, and enhances activation of NF-B. These results suggest that CTLA-4 has a critical role in T cell differentiation and that STAT6-dependent TH2 lineage commitment and stabilization can be bypassed by increasing the strength of signaling through the T cell receptor.