TCR‐independent cytokine stimulation induces non‐MHC‐restricted T cell activity and is negatively regulated by HLA class I

• Published in: European Journal of Immunology 2006-09, Vol.36 (9), p.2347-2358
• Main Authors: von Geldern, Marion, Simm, Barbara, Braun, Monika, Weiß, Elisabeth H., Schendel, Dolores J., Falk, Christine S.
• Format: Article
• Language: English
• Subjects: Cytokines; Cytokines - biosynthesis; Cytokines - immunology; Cytotoxic T cells; Cytotoxicity, Immunologic; Histocompatibility Antigens Class I - immunology; Humans; Lymphocyte Activation - immunology; Major Histocompatibility Complex - immunology; MHC; Natural killer cells; NK Cell Lectin-Like Receptor Subfamily K; Receptors, Antigen, T-Cell - immunology; Receptors, Immunologic - immunology; Receptors, Interleukin-2 - immunology; Receptors, Natural Killer Cell; T-Lymphocytes - immunology
• ISSN: 0014-2980; 1521-4141; 1365-2567
• DOI: 10.1002/eji.200535387

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 γ‐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‐γ, TNF‐α, IL‐5, IL‐13 and MIP‐1β. 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.