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Augmentation of naive, Th1 and Th2 effector CD4 Responses by IL‐6, IL‐1 and TNF

The role of antigen‐presenting cell (APC)‐derived cytokines in T cell activation is still controversial. Highly purified CD4 T cell populations of the naive and short‐term Th1 and Th2 effector subsets were examined. Stimulation from anti‐CD3 in the absence of APC was used to analyze directly T occurring cell‐mediated effects, and the requirement for co‐signaling was addressed using anti‐CD28. Exogenous IL‐6, IL‐1 and TNF each enhanced proliferation and IL‐2 secretion from naive cells, although IL‐6 was most active in this regard. Peak responses, however, were obtained with IL‐1 or TNF in combination with IL‐6 resulting in up to 11‐fold increases in IL‐2 secretion. Enhanced naive T cell responses were only observed with anti‐CD3 and anti‐CD28, suggesting that co‐signaling through surface‐bound receptors was required to initiate IL‐2 production. Although the cytokines enhanced naive activation, little effect was seen on differentiation into effector populations. IL‐6 alone, or in combination, partially suppressed effectors secreting IFN‐γ, but did not promote generation of effectors secreting IL‐4. In contrast to reports on cloned cell lines, IL‐6, TNF and IL‐1 had enhancing activities on all cytokines elicited from already generated Th1 and Th2 effector populations. Again combinations of IL‐6, TNF and IL‐1 were most effective and generally required CD28 signaling. Induced responses with preexisting effector cells were far less than with naive cells and predominantly directed at augmenting IFN‐γ and IL‐5 secretion rather than IL‐2 and IL‐4. These studies show that APC‐derived cytokines can promote T cell responses directly but largely after co‐stimulation from accessory molecule co‐receptors, that the effect is not specific for one T cell subset or cytokine, and that the naive T cell is the main target of action.