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IL-33 Enhances IFNγ and TNFα Production by Human MAIT Cells: A New Pro-Th1 Effect of IL-33
Authors:Mourad Azzout  Cline Dietrich  Franois Machavoine  Pauline Gastineau  Alix Bottier  Guillaume Lezmi  Maria Leite-de-Moraes
Affiliation:1.Laboratory of Immunoregulation and Immunopathology, INEM (Institut Necker-Enfants Malades), CNRS UMR8253, INSERM U1151, Université de Paris, 75015 Paris, France; (M.A.); (C.D.); (F.M.); (P.G.); (A.B.); (G.L.);2.AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie et Allergologie Pédiatriques, 75015 Paris, France
Abstract:Mucosal-associated invariant T (MAIT) cells represent a distinct T cell population restricted by the MHC-class-I-related molecule, MR1, which recognizes microbial-derived vitamin B2 (riboflavin) metabolites. Their abundance in humans, together with their ability to promptly produce distinct cytokines including interferon γ (IFNγ) and tumor necrosis factor α (TNFα), are consistent with regulatory functions in innate as well as adaptive immunity. Here, we tested whether the alarmin interleukin 33 (IL-33), which is secreted following inflammation or cell damage, could activate human MAIT cells. We found that MAIT cells stimulated with IL-33 produced high levels of IFNγ, TNFα and Granzyme B (GrzB). The action of IL-33 required IL-12 but was independent of T cell receptor (TCR) cross-linking. MAIT cells expressed the IL-33 receptor ST2 (suppression of tumorigenicity 2) and upregulated Tbet (T-box expressed in T cells) in response to IL-12 or IL-33. Electronically sorted MAIT cells also upregulated the expression of CCL3 (Chemokine C-C motif ligand 3), CD40L (CD40 Ligand), CSF-1 (Colony Stimulating Factor 1), LTA (Lymphotoxin-alpha) and IL-2RA (IL-2 receptor alpha chain) mRNAs in response to IL-33 plus IL-12. In conclusion, IL-33 combined with IL-12 can directly target MAIT cells to induce their activation and cytokine production. This novel mechanism of IL-33 activation provides insight into the mode of action by which human MAIT cells can promote inflammatory responses in a TCR-independent manner.
Keywords:IL-33  IL-12  inflammation  MAIT cells  innate-like T cells
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