Presence or absence of TGF-beta determines IL-4-induced generation of type 1 or type 2 CD8 T cell subsets.
CD8+ T cells often differentiate into highly cytotoxic cells, secreting a Th1-like or type 1 cytokine pattern characterized by the production of IFN-gamma. However, cytotoxic, and in some reports, noncytotoxic, type 2 cells that secrete IL-4, IL-5, or IL-10 instead of IFN-gamma, can be generated when CD8+ T cells are primed in the presence of IL-4. Here, we show that IL-4 can also generate typical CD8 type 1 responses. Indeed, while presence of TGF-beta biases the development of CD8 T cells that, then, produce little cytolytic activity and IFN-gamma, addition of IL-4 results in the recovery of cytotoxicity and IFN-gamma production. The cooperative effects of TGF-beta and IL-4 imply dual functions, not only for IL-4, but also for TGF-beta. Indeed, depending on the presence or absence of IL-4, TGF-beta either inhibits or induces the generation of type 1 CD8+ T cells. Physiologically, the ratio of local IL-4/TGF-beta concentration may therefore be a critical element in determining the outcome of T cell responses to pathogen and autoantigens. It allows CD8 T cells to switch from an immunotolerant state in the presence of only TGF-beta or IL-4, to an immunocompetent proinflammatory type 1 state in the absence or presence of both cytokines.
Erard
F
F
Laboratoire d'Immunologie, Institut de Recherches Cliniques de Montréal, Canada. erardf@ircm.umontreal.ca
Garcia-Sanz
J A
JA
Moriggl
R
R
Wild
M T
MT
D000818:Animals; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation / Q000276:immunology; D004357:Drug Synergism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*
D016827:CD8 Antigens; D007166:Immunosuppressive Agents; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D015847:Interleukin-4