The role of CTLA-4 in regulating Th2 differentiation

To examine the role of CTLA-4 in Th cell differentiation, we used two newly generated CTLA-4-deficient (CTLA-4(-/-)) mouse strains: Do11.10 CTLA-4(-/- ) mice carrying a class II restricted transgenic TCR specific for OVA, and mice lacking CTLA-4, B7.1 and B7.2 (CTLA-4(-/-) B7.1/B7.2(-/-)). When purif ied naive CD4(+) DO11.10 T cells from CTLA-4(-/-) and wild-type mice were p rimed and restimulated in vitro with peptide Ag, CTLA-4(-/-) DO11.10 T cell s developed into Th2 cells, whereas wild-type DO11.10 T cells developed int o Th1 cells. Similarly, when CTLA-4(-/-) CD4+ T cells from mice lacking CTL A-4, B7.1, and B7.2 were stimulated in vitro with anti-CD3 Ab and wild-type APC, these CTLA-4(-/-) CD4+ T cells produced IL-4 even during the primary stimulation, whereas CD4(+) cells from B7.1/B7.2(-/-) mice did not produce IL-4, Upon secondary stimulation, CD4+ T cells from CTLA-4(-/-) B7.1/R7.2(- /-) mice secreted high levels of IL-4, whereas CD4(+) T cells from B7.1/B7. 2(-/-) mice produced IFN-gamma In contrast to the effects on CD4(+) The dif ferentiation, the absence of CTLA-4 resulted in only a modest effect on T c ell proliferation, and increased proliferation of CTLA-4(-/-) CD4(+) T cell s was seen only during secondary stimulation in vitro, Administration of a stimulatory anti-CD28 Ab in vivo induced IL-4 production in CTLA-4(-/-) B7. 1/B7.2(-/-) but not wiId-tyrpe mice. These studies demonstrate that CTLA-4 is a critical and potent inhibitor of Th2 differentiation. Thus, the B7-CD2 8/CTLA-4 pathway plays a critical role in regulating Th2 differentiation in two ways: CD28 promotes Th2 differentiation while CTLA-4 limits Tb2 differ entiation.