Components of an antigen‐/T cell receptor‐independent pathway of lymphokine production

Abstract

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.

The CD2 and CD28 adhesion molecules induce long‐term autocrine proliferation of CD4+ T cells

“…These results further confirm the difference in the regulation of the production of various cytokines by Tcells according to the stimuli [26,27]. CSF-1 and TNF-a require only minimal Tcell stimulation [17, 261 whereas lymphokines such as IL-2 and IL-4 require an optimal Tcell stimulation provided here by CD2 or coated CD3 in association with CD28.…”

The interleukin‐12 subunit p40 specifically inhibits effects of the interleukin‐12 heterodimer

“…Because endogenous release of TSFAL-12 is probably one component of the alternative pathway of IFN-y production by Thl cells stimulated with macrophages and IL-2 [15], we tested IL-12p40 for its inhibitory capacity in this assay system. Indeed, the IL-12 subunit p40 reduced IFN-y production of Thl cells activated by bone marrow-derived macrophages and IL-2 or macrophages, IL-2 and IL-12 in a concentration-dependent manner (Fig.…”

“…Endogenous release of IL-12 in combination with a second macrophagederived accessory signal and IL-2 is probably involved in the synthesis of IFN-y in the alternative pathway [14]. The combination of IL-2 + IL-12 (or TSF) can also trigger the synthesis of IFN-y by NK cells present in mouse spleen cells [15] or human PBMC [2, lo].…”

Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist.

“…So TNF-a is necessary but not sufficient in stimulating NK-cell production of IFN-y. Recently, interleukin (IL) 12 has been cloned (5, 6) and described by several laboratories (7)(8)(9) as a potent inducer of IFN-yproduction by NK cells and various T cells. Also, IL-2 acts synergistically with IL-12 in the stimulation of IFN-y.…”

“…Although TNF and IL-2 augmented IFN-y production mediated by IL-12, IL-12 alone induced low levels of IFN-y. IL-12 has been shown to act synergistically with IL-2 to produce IFN-'y in other systems as well (7)(8)(9). Likewise, the effects of anti-IL-10 indicated that this cytokine was being stimulated by hk-LM to inhibit IFN-y production.…”