STRENGTH OF ICR SIGNAL DETERMINES THE COSTIMULATORY REQUIREMENTS FOR TH1 AND TH2 CD4(-CELL DIFFERENTIATION() T)

Differentiation of naive CD4 T cells into cytokine-secreting effector Th1 and Th2 cells is influenced by several factors. We have previously reported that the affinity of antigen for TCR and antigen dose can in fluence the differentiation of Th1 and Th2 cells. Several in vitro and in vivo models have demonstrated a role for the costimulatory molecul es, B7-1 (CD80) and B7-2 (CD86), in the generation of distinct effecto r T cell responses. To determine whether the strength of TCR signaling controls the involvement of CD28 costimulation in selective CD4 T cel l differentiation, naive CD4 T cells bearing a transgenic TCR are prim ed by a weak or strong TCR signal (signal 1) in the presence or absenc e of B7 costimulatory molecules (signal 2). In this system, IL-4-produ cing Th2 cells are generated by priming with a weak but not a strong T CR signal. Th2 cell differentiation is dependent on CD28/B7 interactio ns in that disruption of CD28/B7 interactions inhibits the priming of Th2 cells and cross-linking CD28 with anti-CD28 antibody augments the priming of Th2 cells. In contrast, however, IL-4-producing Th2 cells c annot be generated by priming with a strong TCR signal even in the pre sence of strong costimulation or high doses of IL-2. Thus, our results suggest that naive CD4 T cells are receptive to CD28-dependent IL-4 p roduction only if they receive a weak TCR signal.