Gamma c cytokines condition the progressive differentiation of CD4+ T cells.
After their initial antigen encounter in the secondary lymphoid organs, activated T cells must receive additional signals in the peripheral tissues to fully differentiate. Here, we provide evidence that gamma(c) cytokines are critical during this process. Using the Marilyn (Ml) T cell antigen receptor (TCR) transgenic model, we show that male skin grafts are tolerated in the absence of gamma(c), but that Ml CD4(+) T cells proliferate normally in response to antigen, traffic to the graft site and recruit an inflammatory response [including natural killer (NK) cells, neutrophils, and macrophages] that is independent of T cell gamma(c) expression. Whereas wild-type T cells demonstrate a progressive differentiation phenotype from the spleen to the tissues, skin-infiltrating effector T cells (CD44(hi)CD62L(lo)) from gamma(c)(-) mice were phenotypically abnormal with reduced ICOS, NKG2D, granzyme B, and IFN-gamma expression. These defects could be mapped to deficiencies in IL-2 and, surprisingly, IL-15. These results define a late checkpoint in T cell differentiation in the tissues where gamma(c) cytokines, including IL-15, authenticate CD4(+) T cell effector functions.
Masse
Guillemette X
GX
Cytokines and Lymphoid Development Unit, Immunology Department, Institut Pasteur, F-75724 Paris, France.
Corcuff
Erwan
E
Strick-Marchand
Hélène
H
Guy-Grand
Delphine
D
Tafuri-Bladt
Anna
A
Albert
Matthew L
ML
Lantz
Olivier
O
Di Santo
James P
JP
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D053804:Granzymes / Q000096:biosynthesis; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000096:biosynthesis; D053646:Interleukin-2 Receptor beta Subunit / Q000096:biosynthesis; D019041:L-Selectin / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000096:biosynthesis; D055607:Receptors, Natural Killer Cell
D016207:Cytokines; D018960:Hyaluronan Receptors; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D019041:L-Selectin; D007371:Interferon-gamma; D053804:Granzymes