IL-4-producing NK T cells are biased towards IFN-gamma production by IL-12. Influence of the microenvironment on the functional capacities of NK T cells.
NK T cells are an unusual T lymphocyte subset capable of promptly producing several cytokines after stimulation, in particular IL-4, thus suggesting their influence in Th2 lineage commitment. In this study we demonstrate that, according to the cytokines present in the microenvironment, NK T lymphocytes can preferentially produce either IL-4 or IFN-gamma. In agreement with our previous reports showing that their IL-4-producing capacity is strikingly dependent on IL-7, CD4-CD8-TCRalphabeta+ NK T lymphocytes, obtained after expansion with IL-1 plus granulocyte-macrophage colony-stimulating factor, produced almost undetectable amounts of IL-4 or IFN-gamma in response to TCR/CD3 cross-linking. However, the capacity of these T cells to produce IFN-gamma is strikingly enhanced when IL-12 is added either during their expansion or the anti-CD3 stimulation, while IL-4 secretion is always absent. A similar effect of IL-12 on IFN-gamma production was observed when NK T lymphocytes were obtained after expansion with IL-7. It is noteworthy that whatever cytokines are used for their expansion, IL-12 stimulation, in the absence of TCR/CD3 cross-linking, promotes consistent IFN-gamma secretion by NK T cells without detectable IL-4 production. Experiments in vivo demonstrated a significant upregulation of the capacity of NK T cells to produce IFN-gamma after anti-CD3 mAb injection when mice were previously treated with IL-12. In conclusion, we provide evidence that the functional capacities of NK T cells, which ultimately will determine their physiological roles, are strikingly dependent on the cytokines present in their microenvironment.
Leite-De-Moraes
M C
MC
Centre National de la Recherche Scientifique URA 1461, Université René Descartes, Paris, France. leite@infobiogen.fr
Moreau
G
G
Arnould
A
A
Machavoine
F
F
Garcia
C
C
Papiernik
M
M
Dy
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D006224:Cricetinae; D016207:Cytokines / Q000502:physiology; D007274:Injections, Intraperitoneal; D007369:Interferon Inducers / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D007369:Interferon Inducers; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma