COMPONENTS OF AN ANTIGEN-T-CELL RECEPTOR-INDEPENDENT PATHWAY OF LYMPHOKINE PRODUCTION

The general way to induce the synthesis of lymphokines by T cells is the stimulation through the T cell receptor (TcR) complex which results in an increase of intracellular [Ca2+] and in the activation of a tyrosine kinase as well as of protein kinase C. Lymphokine production induced via the TcR is inhibited by the immunosuppressive drug cyclosporin A (CsA). However, an alternative pathway of lymphokine production exists. Several T lymphocyte clones can synthesize interferon-gamma (IFN-gamma), granulocyte-monocyte colony-stimulating factor, and small amounts of interleukin (IL3) when stimulated with syngeneic or allogeneic accessory cells (AC) plus IL2. In contrast to the TcR pathway the alternative pathway does not require a rise of intracellular [Ca2+] and is insensitive to the effects of CsA. In this report we provide evidence for the involvement of T cell-stimulating factor (TSF) - a probably novel murine cytokine - in the alternative pathway of lymphokine production. It is shown that fixation of the AC with carbodiimide or treatment of the AC with UV light greatly reduces their capacity to induce (in combination with IL2) the synthesis of IFN-gamma by T cells. This function is restored by addition of TSF. Moreover, TSF alone (without IL2) in combination with fixed AC can induce the synthesis of substantial amounts of IFN-gamma. Furthermore, TSF in combination with IL2 can stimulate freshly isolated spleen cells to produce IFN-gamma. The target cell resides probably in the non-B cell, non-T cell population.