Abstract
Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor β chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1β induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1β to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1βR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.
Highlights
Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear
We show that CD122 (IL-2/IL-15Rβ) is selectively expressed in MAIT1 cells and is critical for MAIT1 but not MAIT17 cell differentiation by transducing signals from both IL2 and IL-15 that lead to mTORC1 activation, T-bet upregulation, and subsequent enhancement of MAIT1 cell proliferation and survival
IFN-γ was detected in the CD122−inducible costimulatory (ICOS)+ cell supernatant, its concentration was much lower than the CD122+ICOS− cells and could be resulted from contamination of MAIT1 cells
Summary
Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. We report that IL-2/IL-15 receptor β chain and inducible costimulatory (ICOS) serve as lineage-specific markers for IFNγ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are important for their differentiation, respectively Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. Additional signal pathways downstream of iVα19TCR and other costimulatory and cytokine signals that regulate MAIT cell development are poorly understood It was until the recent development of MR1 tetramers loaded with the riboflavin-derived 5-OP-RU ligand that it became possible to detect MAIT cells in mice[11]. MTOR is a serine/threonine kinase that plays critical roles in diverse cellular processes, such as metabolism, proliferation, growth, autophagy, and differentiation It signals through two complexes, mTORC1 and mTORC2 that contain essential adapter molecules Raptor and Rictor, respectively.
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