Qa-2lo expression reveals a small subset of peripheral naïve CD4+ T cells with heightened IL-4 inducibility

Both peripheral and thymus NK1-CD4+CD8-CD44low T cells displayed an age-associated increase in Qa-2 expression, but the magnitude of the increase was relatively small for NK1-CD4+CD8-CD44low thymocytes and was much more pronounced for peripheral NK1-CD4+CD8-CD44low T cells. Qa-2 expression was uniformly high for the vast majority of NK1-CD4+CD8-CD44low T cells obtained from peripheral tissues and organs. On the other hand, Qa-2 expression was weaker and more heterogeneous for NK1-CD4+CD8-CD44low T cells from the thymus. An inverse correlation between the level of Qa-2 expression and IL-4 inducibility was found for both thymus and spleen NK1-CD4+CD8-CD44low T cells, although the level of IL-4 inducibility was significantly higher for cells from the thymus than the spleen. Similar enrichment of IL-4 inducibility in peripheral NK1-CD4+CD8-CD44low T cells was observed in mice carrying disrupted p59fyn or il4r genes. Isolation of the Vb(2/7/8)+ subset from spleen Qa-2lowNK1-CD4+CD8-CD44low T cells resulted in further enrichment in IL-4 inducibility. In the absence of exogenously added cytokines, TCR-stimulated IL-4 production by spleen Qa-2lowNK1-CD4+8-CD44low T cells promoted their own differentiation toward Th2 effectors in an IL-4-dependent manner. Under Th1 priming conditions, both Qa-2low and Qa-2hi subsets of spleen NK1-CD4+CD8-CD44low T cells differentiated into high level IFNg-producing Th1 effectors. Under Th2 priming conditions, both Qa-2low and Qa-2hi subsets of spleen NK1-CD4+CD8-CD44low T cells differentiated into high level IL-4-produccing Th2 effectors. Thus, the generally accepted low level IL-4 inducibility by naïve CD4+ T cells is due to high level IL-4 inducibility by a small subpopulation of peripheral CD4+ T cells and not due to low level IL-4 inducibility by all or most naïve CD4+ T cells. Furthermore, this small subset of Qa-2lowNK1-CD4+CD8-CD44low T cells, by virtue of its naïve phenotype, prompt IL-4 inducibility, and distribution in the periphery, is expected to play a significant role in the initial stages of immune response by rapidly releasing IL-4 which may in turn direct Th2 response and other IL-4-dependent processes.