TCR-independent cytokine stimulation induces non-MHC-restricted T cell activity and is negatively regulated by HLA class I.
Recent evidence suggests that the functional status of T cells activated independently from their TCR differs substantially from classical MHC-restricted T cells. Here, we show that TCR-independent, short-term stimulation via the common gamma-chain of the IL-2/IL-15 receptor induces non-MHC-restricted cytotoxicity and sustained cytokine secretion in purified CD4+ or CD8+ T cells. NK-like cytotoxicity is directed against MHC class I-negative targets and can be inhibited by classical and non-classical HLA class I molecules. Known inhibitory receptors, such as CD85j (ILT2) and leukocyte-associated Ig-like receptor-1, are not responsible for this HLA-mediated inhibition. NK-like cytotoxicity can be costimulated by NKG2D (CD314) triggering, but 2B4 (CD244) and DNAM-1 (CD226) are not involved. NK-like T cells display an activated phenotype and secrete various cytokines, including IFN-gamma, TNF-alpha, IL-5, IL-13 and MIP-1beta. Under normal conditions, HLA class I-mediated inhibition may function as a safety mechanism to prevent unbalanced cytokine production and effector killing mechanisms by T cells that were activated independently from their TCR. Non-MHC-restricted activity represents a functional status rather than a property of distinct T cell subpopulations. Thus, cytokine-induced, non-MHC-restricted T cells may be relevant in immune responses against tumors showing aberrant MHC expression through their capacities of cytokine production and direct tumor cell eradication.
von Geldern
Marion
M
Institute of Molecular Immunology, GSF National Research Center for Environment and Health, Munich, Germany.
Simm
Barbara
B
Braun
Monika
M
Weiss
Elisabeth H
EH
Schendel
Dolores J
DJ
Falk
Christine S
CS
D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D055607:Receptors, Natural Killer Cell; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D055607:Receptors, Natural Killer Cell