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-gamma, 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-gamma 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.
Joseph
S B
SB
La Jolla Institute for Allergy and Immunology, Division of Immunochemistry, San Diego, USA.
Miner
K T
KT
Croft
M
M
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017951:Antigen Presentation; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002454:Cell Differentiation; D004357:Drug Synergism; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D015398:Signal Transduction; D018417:Th1 Cells / Q000187:drug effects* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D018106:CD28 Antigens; D017252:CD3 Complex; D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D008222:Lymphokines; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma