CD4 ligation promotes the IL-4-independent development of IL-4-producing clones from naive CD4(+) T cells

The signals that trigger IL-4-independent IL-4 synthesis by conventional CD 4(+) T cells are not yet defined. In this study, we show that coactivation with anti-CD4 mAb can stimulate single naive CD4(+) T cells to form IL-4-pr oducing clones in the absence of APC and exogenous IL-4, independently of e ffects on proliferation. When single CD4(+) lymph node cells from C57BL/6 m ice were cultured with immobilized anti-CD3e mAb and IL-2, 65-85% formed cl ones over 12-14 days. Coimmobilization of mAb to CD4, CD11a, and/or CD28 in creased the size of these clones but each exerted different effects on thei r cytokine profiles. Most clones produced IFN-gamma and/or IL-3 regardless of the coactivating mAb. However, whereas 0-6% of clones obtained with mAb to CD11a or CD28 produced IL-4,10-40% of those coactivated with anti-CD4 mA b were IL-4 producers. A similar response was observed among CD4(+) cells f rom BALB/c mice. Most IL-4-producing clones were derived from CD4(+) cells of naive (CD44(low) or CD62L(high)) phenotype and the great majority coprod uced IFN-gamma and IL-3. The effect of anti-CD4 mAb on IL-4 synthesis could be dissociated from effects on clone size since anti-CD4 and anti-CD11a mA b stimulated formation of clones of similar size which differed markedly in IL-4 production. Engagement of CD3 and CD4 in the presence of IL-2 is ther efore sufficient to induce a substantial proportion of naive CD4(+) T cells to form IL-4-producing clones in the absence of other exogenous signals, i ncluding IL-4 itself.