Chronically stimulated human MAIT cells are unexpectedly potent IL‐13 producers

Abstract

Mucosal‐associated invariant T (MAIT) cells are unconventional T cells that recognize antigens derived from riboflavin biosynthesis. In addition to anti‐microbial functions, human MAIT cells are associated with cancers, autoimmunity, allergies and inflammatory disorders, although their role is poorly understood. Activated MAIT cells are well known for their rapid release of Th1 and Th17 cytokines, but we have discovered that chronic stimulation can also lead to potent interleukin (IL)‐13 expression. We used RNA‐seq and qRT‐PCR to demonstrate high expression of the IL‐13 gene in chronically stimulated MAIT cells, and directly identify IL‐13 using intracellular flow cytometry and multiplex bead analysis of MAIT cell cultures. This unexpected finding has important implications for IL‐13‐dependent diseases, such as colorectal cancer (CRC), that occur in mucosal areas where MAIT cells are abundant. We identify MAIT cells near CRC tumors and show that these areas and precancerous polyps express high levels of the IL‐13 receptor, which promotes tumor progression and metastasis. Our data suggest that MAIT cells have a more complicated role in CRC than currently realized and that they represent a promising new target for immunotherapies where IL‐13 can be a critical factor.

MAIT Cells Come to the Rescue in Cancer Immunotherapy?

“…In colon cancer patients, MAIT cells were found to infiltrate tumor tissue [32,58,59,103,104]. This is in accordance with the pattern of tissue-homing chemokine receptors of the MAIT cells isolated from the peripheral blood and the intestinal mucosa of colon cancer [59].…”

“…The functional assessment of tumor-infiltrating MAIT cells revealed an enrichment in IL-17-producing and a depletion in IFN-γ-producing subpopulations compared to the unaffected colonic tissue of the same patients [58]. Furthermore, chronic stimulation of MAIT cells results in an increase of IL-13 gene expression and consequent IL-13 production [32]. This finding is particularly interesting in the context of high expression of IL-13 receptor on precancerous intestinal polyps and colorectal cancer tissue [32].…”

“…Studies on MAIT cell development and effector functions point towards their close relationship Upon activation, MAIT cells robustly release perforin and granzymes and produce the pro-inflammatory cytokines TNFα, IFNγ, and IL-17A as well as the potent granulocyte stimulation factor MIP-1. Production of other cytokines such as IL-22, IL-13, IL-26, or IL-2 was described in the context of different cytokine milieus and tissue subsets [29][30][31][32]. The rapid MAIT cell response to pathogenic bacteria is fully MR1-dependent [33], but the long-range activation is shaped by the combination and the amount of other stimuli [34,35].…”

MAIT cells regulate NK cell mediated tumor immunity

“…IFNγ and TNF) and pro-tumor activity (e.g. IL-17α, IL-22 and IL-13) (6,22,25). Therefore, although it is plausible that MAIT cells may become activated within the TME, their contribution to anti-tumor immune responses remains unclear due to this diverse range of effector functions.…”

“…The observation that MAIT cell-deficient mice have enhanced NK cells is reminiscent of a previous report showing that NKT cell-deficient mice have increased levels of MAIT cells (47). It is possible that MAIT cells actively control NKcell function via the production of inhibitory cytokines or other factors, such as IL-13, which was recently shown to be abundantly produced by MAIT cells following chronic stimulation(25).…”