The capacity of the natural ligands for CD28 to drive IL-4 expression in naı̈ve and antigen-primed CD4 and CD8 T cells

The B7/CD28 costimulatory pathway plays a critical role in T cell activation including Th1/Th2 differentiation. However, little is known about whether CD28 costimulation favors polarization of either Th1 and Th2 or both. Here, we show a critical role of the natural ligands for CD28 molecules (B7.2–Ig or B7.1–Ig fusion proteins), particularly in the induction of type 2 T cell polarization. Upon TCR-triggering with suboptimal doses of anti-CD3, costimulation of naı̈ve CD4 T cells with anti-CD28 mAb or B7–Ig fusion proteins led to comparable levels of IFN-c production. Naı̈ve T cells could produce IL-4 when CD28 costimulation was done with B7–Ig, but not with anti-CD28. IL-4-selective upregulation was also observed when T cells from anti-OVA TCR transgenic mice were stimulated with OVA in the presence of B7–Ig. Correlating with IL-4 expression, GATA-3 expression was induced much more potently by costimulation with B7–Ig than with anti-CD28 mAb, while T-bet induction by these two costimulatory reagents was comparable. This B7 effect was also applied for naı̈ve and antigen-primed CD8 T cells: IL-4-expressing CD8 T cells were generated when naı̈ve and alloantigen-primed T cells were stimulated with anti-CD3 and recall antigens, respectively, in the presence of B7–Ig costimulation. Importantly, such CD8 T cell differentiation required the coexistence of CD4 T cells during the initial TCR stimulation. These observations indicate that both type 2 CD4 and CD8 T cell polarizations are efficiently induced via costimulation of CD28 with its natural ligands, although the differentiation of CD8 T cells is dependent on CD4 cells.