COSTIMULATION OF HUMAN CD4-LYMPHOCYTES WITH B7 AND LYMPHOCYTE FUNCTION-ASSOCIATED ANTIGEN-3 RESULTS IN DISTINCT CELL ACTIVATION PROFILES( T)

This study describes the distinct roles of B7 and LFA-3 in the regulat ion of T cell responses. Activation of CD4(+) T cells with Chinese ham ster ovary (CHO)-DR4/B7 and CHO-DR4/LFA-3 cells that present the super antigen staphylococcal enterotoxin A resulted in significant T cell pr oliferation and substantial production of TNF and IFN-gamma. Strong IL -2 production was recorded in B7-costimulated, but not LFA-3-costimula ted, cultures. The presence of B7 induced a more vigorous and prolonge d proliferative T cell response compared with LFA-3 costimulation. In contrast, LFA-3 was more efficient than B7 in mediating cell adhesion of CD4(+) T cells. Costimulation with the CHO-DR4/B7/LFA-3 triple tran sfectant resulted in enhanced cell adhesion, proliferation, and cytoki ne production compared with either DR4/B7 or DR4/LFA-3 alone. Optimal production of IL-2 by naive and memory CD4(+) T cells was seen only wh en cells were costimulated with B7, whereas IFN-gamma production was i nduced in memory cells by both LFA-3 and B7. The Jurkat T cell line re sponded to CHO-DR4/B7/LFA-3 in a manner similar to peripheral blood CD 4(+) T cells. Reverse transcriptase-PCR analysis of Jurkat cells stimu lated with staphylococcal enterotoxin E and the different CHO transfec tants revealed that the cooperative effect of B7 and LFA-3 on IL-2 pro duction was also seen at the mRNA level. The large amounts of IL-2 pro duced by B7 costimulation indicate a. paracrine function of the B7/CD2 8 pathway, whereas the LFA-3/CD2 pathway provides strong adhesion and may facilitate autocrine T cell expansion. Combined expression of the B7 and LFA-3 molecules seems to provide an optimal Ag-presenting funct ion that ensures strong adhesion and optimal signal transduction.