Genetic background influences Th cell differentiation by controlling the capacity for IL-2-induced IL-4 production by naive CD4+ T cells

Comparative studies using Th2-prone BALB/c and Th1-prone C57BL/6 mice were performed to clarify the influence of genetic background on Th cell differentiation. The results showed IL-4, the production of which is induced by IL-2, to be much more abundantly produced by BALB/c naive CD4+ T cells than by C57BL/6 naive CD4+ T cells, thereby leading to a tendency for differentiation toward Th2 in BALB/c naive CD4+ T cells. This difference in IL-4 production between the two naive CD4+ T cells appeared to be attributable to specific intracellular signaling events. Signal transducer and activator of transcription 5 (STAT5) was preferentially activated by IL-2 in CD4+ T cells developing in BALB/c in contrast to the corresponding cells in C57BL/6. In addition, IL-4 also induced stronger STAT5 activation in CD4+ T cells developing in BALB/c than in those developing in C57BL/6, whereas STAT6 was equally activated in these two cells. Further results supported the involvement of STAT5 in the difference in Th cell differentiation between BALB/c and C57BL/6 naive CD4+ T cells. STAT5A−/− naive CD4+ T cells with the BALB/c genetic background showed markedly less IL-2-induced IL-4 production than BALB/c naive CD4+ T cells. Conversely, forced expression of the constitutively active forms of STAT5A and STAT5B in C57BL/6 naive CD4+ T cells promoted the differentiation of Th2 cells. Thus, our results indicate IL-2-induced IL-4 production by naive CD4+ T cells, in which STAT5 activation is involved and directly controlled by the genetic background, to influence Th cell differentiation in murine strains.