A bidirectional regulatory network involving IL 2 and IL 4 in the alternative CD2 pathway of T cell activation

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Abstract
In this study we examined the effect of interleukin 4 (IL 4) on T cell activation and proliferation via the alternative CD2 pathway. To this end highly purified human resting T cells were cultured with a stimulating pair of anti‐CD2 monoclonal antibodies in the absence of accessory signals from monocytes. Addition of either recombinant (r)IL 2 or rIL 4 resulted in proliferation of the anti‐CD2‐stimulated T cells. The growth‐promoting effect of rIL 4 on preactivated T cells was shown to be partly a direct effect. rIL 4 also induced IL 2 production and, as a consequence, the effect of rIL 4 on T cell growth was enhanced by endogenously produced IL 2. Moreover, rIL 4 acted in synergy with exogenously added rIL 2 in promoting growth of anti‐CD2‐stimulated T cells. The synergistic effect of IL 2 and IL 4 could be explained by IL 2‐induced up‐regulation of IL 4 responsiveness. In contrast, preincubation with rIL 4 did not enhance IL2 responsiveness and rIL2 but not rIL4 up‐regulated IL 2R expression on anti‐CD2‐stimulated T cells. Finally we could demonstrate that monocyte‐produced cytokines (IL 1 and IL 6) enhance the proliferative response to rIL 4 of anti‐CD2‐stimulated T cells. It can be concluded that IL 4 can act as a paracrine growth factor for T cells activated in the alternative CD2 pathway, and that it acts synergistically with IL 2, IL 1 and IL 6. Moreover, IL 4 is a helper signal for IL 2 production. Thus, IL 2 and IL 4 are involved in a bidirectional regulatory network, with IL 4 as an inducer of IL 2 production, and IL 2 as an enhancer of IL 4 responsiveness.

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