Cytokine deprivation of naive CD8+ T cells promotes minimal cell cycling but maximal cytokine synthesis and autonomous proliferation subsequently: a mechanism of self-regulation.
Naive CD8+ T cells differentiate into effectors secreting various cytokines that aid their function. IL-2, but not IL-15, promoted this differentiation of naive CD8+ T cells into effectors. However, the amount of IL-2 present during differentiation had a dichotomous effect on their subsequent function. High concentrations of IL-2 enhanced proliferation and cell cycling initially, but the effectors subsequently failed to produce cytokines and proliferate autonomously, although CD28 expression was maintained. In contrast, suboptimal amounts of IL-2 during priming promoted apoptosis, little proliferation and cell cycling, yet the CD8+ effectors generated produced high levels of cytokines and proliferated autonomously. Interestingly, the effects of IL-2 on naive CD8+ T cells were totally opposite those on naive CD4+ T cells. Although IL-2 impaired cytokine synthesis by CD8+ T cells, the expression of LFA1 and CD44 as well as Fas-dependent cytotoxicity were enhanced. However, loss of cytokine synthesis was not due to increased cytotoxicity, as inhibition occurred even in the absence of perforin/FasL. Interestingly, CD8+ effectors secreting reduced amounts of cytokines exhibited enhanced IL-2Ralpha, but reduced IL-2Rbeta, expression. Furthermore, sorted CD8+ IL-2Ralphahigh cells secreted less cytokines than IL-2Ralphalow cells. These results suggest that the presence of excessive IL-2 during the activation of naive CD8+ T cells, while promoting cell cycling initially, may compromise long-term immunity.
Sad
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S
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario. subash.sad@nrc.ca
Krishnan
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D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D002453:Cell Cycle / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D002469:Cell Separation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000172:deficiency; D005260:Female; D005434:Flow Cytometry; D019409:Interleukin-15 / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D000276:Adjuvants, Immunologic; D016207:Cytokines; D019409:Interleukin-15; D007376:Interleukin-2; D008565:Membrane Proteins