Naive human T cells can be a source of IL-4 during primary immune responses

IL-4 plays a key role in driving the differentiation of CD4+ Th precursors into Th2 cells, both in mice and in humans. The source of IL-4 during primary immune responses is, however, still debated. When IL-4 consumption in in vitro T cell cultures was blocked with a MoAb to the IL-4 receptor alpha-chain (IL-4Ralpha), it became evident that freshly isolated naive (CD45RO-) CD4+ T cells from adults or cord blood produce IL-4 upon activation with anti-CD3 and CD80. IL-4 production by naive T cells is strictly IL-2-dependent. Endogenous IL-4 activity in naive CD4+ T cell cultures modulates the production of interferon-gamma (IFN-gamma) on the one hand and IL-5 and IL-13 on the other hand in opposite directions, and it is partly responsible for the low IFN-gamma production by cord blood T cells. Comparison of the ratio of IL-4/IFN-gamma in supernatants of T cell cultures reveals a skewing towards IL-4 production by cord blood T cells, while naive T cells from (non-atopic) adults predominantly produce IFN-gamma. We conclude that CD4+ naive T cells can produce IL-4 without the need for Th2 differentiation, and therefore that they can be the initial source of IL-4 required at the time of priming for T cell differentiation into Th2 cells.