Interleukin (IL) 4, in the absence of antigen stimulation, induces an anergy-like state in differentiated CD8+ TC1 cells: loss of IL-2 synthesis and autonomous proliferation but retention of cytotoxicity and synthesis of other cytokines.
Naive T cells in the periphery mainly secrete interleukin (IL) 2 upon activation. After stimulation in the presence of appropriate costimulators, both CD4+ and CD8+ T cells differentiate into effector cells secreting distinct T helper (Th) 1- and Th2-like cytokine patterns. Subsequent to differentiation, both CD4+ (Th1 and Th2) and CD8+ (TC1 and TC2) cells are stable and cannot be induced to differentiate into the opposite pattern or revert to the naive cytokine secretion pattern. We now show that IL-4 caused committed TC1 bulk populations or clones to lose the ability to synthesize IL-2. The cells retained the ability to secrete interferon (IFN) gamma, granulocyte/macrophage colony-stimulating factor, and tumor necrosis factor, did not synthesize any Th2 cytokines, and did not alter cell surface marker expression. IL-4 rapidly inhibited IL-2-synthesizing ability in the absence or presence of antigen-presenting cells, thus demonstrating that IL-4 acted directly on TC1 cells. The defect in IL-2 synthesis could not be reversed by subsequent stimulation with potent antigen-presenting cells in the presence of IL-2 and anti-IL-4, or with anti-CD3 plus anti-CD28 antibodies. Both IL-2+ and IL-2- TC1 cells were strongly cytotoxic toward allogeneic but not syngeneic targets. However, IL-2- TC1 cells were unable to proliferate unless exogenous IL-2 was provided. TC1 cells that lose IL-2 synthesis but retain IFN-gamma synthesis and cytotoxicity may be similar to the "anergic" cells induced by stimulation of CD4+ or CD8+ cells in the absence of costimulators. These results suggest that during a mixed type 1/type 2 response in vivo, IL-4 may induce the IL-2+ TC1-->IL-2-TC1 conversion, and thus curtail the expansion of the TC1 response without impairing short-term effector function.
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Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada.
Mosmann
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D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000187:drug effects*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007376:Interleukin-2; D008222:Lymphokines; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor