Abstract
Mucosal-associated invariant T (MAIT) cells all express a semi-invariable T cell receptor recognizing microbial metabolites presented on the MHC class I-like molecule MR1. Upon activation, they rapidly secrete cytokines and increase their cytotoxic potential. We showed recently that MAIT cells with Th1 phenotype accumulate in human colon adenocarcinomas. Here, we investigated the cytotoxic potential of tumor-infiltrating MAIT cells in colon adenocarcinomas, and to what extent it may be affected by the tumor microenvironment. Activation of MAIT cells from tumors induced increased Granzyme B, and to a lesser extent, perforin expression. Degranulation was assessed by surface expression of CD107a, and was also seen in response to cognate antigen recognition. The cytotoxic potential of tumor-associated MAIT cells was very similar to that of MAIT cells from unaffected colon. MAIT cells were also identified by immunofluorescence in direct contact with tumor cells in sections from colon cancer specimens. To summarize, tumor-associated MAIT cells from colon tumors have strong cytotoxic potential and are not compromised in this regard compared to MAIT cells from the unaffected colon. We conclude that MAIT cells may contribute significantly to the protective immune response to tumors, both by secretion of Th1-associated cytokines and by direct killing of tumor cells.
Highlights
Mucosal-associated invariant T (MAIT) cells are semi-invariant T cells expressing a T cell receptor (TCR) comprising Vα7.2 joined with Jα33, which in turn are combined with a limited selection of Vβ chains [1, 2]
To determine if tumor-associated MAIT cells may contribute to anti-tumor cytotoxicity, we examined the cytotoxic potential of freshly isolated MAIT cells from colon tumors and unaffected colon tissue as well as peripheral blood from the same patients
MAIT cells were defined as CD45+CD3+ TCR γ/δ–CD4–Vα7.2+CD161high cells, and the gating strategy is shown in Supplementary Figure 1A
Summary
Mucosal-associated invariant T (MAIT) cells are semi-invariant T cells expressing a T cell receptor (TCR) comprising Vα7.2 joined with Jα33, which in turn are combined with a limited selection of Vβ chains [1, 2]. The resulting TCR recognizes microbial metabolites of vitamin B2 (riboflavin) which are synthesized by many bacterial species, as well as fungi. These metabolites are presented by the highly conserved and invariant MHC-Ib major histocompatibility complex-related protein 1 (MR1) molecule, present on both classical antigen-presenting cells and different types of epithelial cells [3, 4]. MAIT cells efficiently leave the circulation and enter inflamed tissues without the need for phenotypic changes or activation in lymphoid organs [7]. When activated by cognate antigen recognition or by combinations of cytokines, MAIT cells rapidly secrete cytokines and up-regulate cytotoxicity-related molecules like Granzyme B (GrB) [8,9,10]. MAIT cells have been implicated in immunopathology in autoimmune diseases [17, 18], inflammatory bowel disease [19, 20] and the immune dysregulation in adipose tissues of patients suffering from type 2 diabetes [21]
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