Interleukin-2 induces tumor necrosis factor-alpha production by activated human T cells via a cyclosporin-sensitive pathway.
We examined requirements for TNF-alpha production by purified human blood T cells, completely depleted of monocyte-accessory cells, under different conditions of stimulation. Activation of T cells with immobilized anti-CD3 induced the appearance of mRNA for TNF-alpha and of functionally active TNF-alpha in the culture supernatant. Anti-CD3-induced TNF-alpha production could be inhibited by blocking the IL-2R with a combination of anti-Tac and Mik beta 1 (mAbs against the p55 and p75 chain of the IL-2R respectively) thus indicating an essential role of IL-2 in TNF-alpha induction. When purified T cells were activated with a combination of two anti-CD2 mAbs (9-1 and 9.6), additional signals (rIL-2 or rIL-1 beta or anti-CD28) were required for TNF-alpha mRNA production and protein secretion. rIL-1 beta supported anti-CD2-induced TNF-alpha production indirectly through an IL-2-dependent pathway. These same helper signals also enhanced TNF-alpha production by anti-CD3-stimulated T cells. IL-4, IL-6, GM-CSF and IFN-gamma had no effect on TNF-alpha production by T cells activated via either pathway. Addition of rIL-1 beta alone, rIL-2 alone or endotoxins to resting human T cells did not induce detectable amounts of TNF-alpha. Both helper/inducer CD4(+) and suppressor/cytotoxic CD8(+) subsets of T cells were shown to produce TNF-alpha upon stimulation. We conclude that CD3 or CD2 triggering are not sufficient for TNF-alpha production by T cells, but that the latter is dependent (apparently at the transcriptional level) on the interaction of IL-2 with its functionally active cell surface receptors. We could further demonstrate that TNF-alpha production was completely blocked by cyclosporin A. The inhibitory effect of this agent on TNF-alpha production was also observed in the presence of rIL-2, thus excluding an indirect effect through inhibition of IL-2 production.
Lorré
K
K
Department of Medicine and Pathophysiology, University of Leuven, Belgium.
Fransen
L
L
Ceuppens
J L
JL
D000328:Adult; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D017252:CD3 Complex; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine