Modulation of bacterial metabolism by the microenvironment controls MAIT cell stimulation

Abstract

Mucosal-associated invariant T (MAIT) cells are abundant innate-like T lymphocytes in mucosal tissues and recognize a variety of riboflavin-related metabolites produced by the microbial flora. Relevant issues are whether MAIT cells are heterogeneous in the colon, and whether the local environment influences microbial metabolism thereby shaping MAIT cell phenotypes and responses. We found discrete MAIT cell populations in human colon, characterized by the diverse expression of transcription factors, cytokines and surface markers, indicative of activated and precisely controlled lymphocyte populations. Similar phenotypes were rare among circulating MAIT cells and appeared when circulating MAIT cells were stimulated with the synthetic antigens 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil, and 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil. Furthermore, bacteria grown in colon-resembling conditions with low oxygen tension and harvested at stationary growth phase, potently activated human MAIT cells. The increased activation correlated with accumulation of the above antigenic metabolites as indicated by mass spectrometry. Thus, the colon environment contributes to mucosal immunity by directly affecting bacterial metabolism, and indirectly controlling the stimulation and differentiation of MAIT cells.

The Activation of Mucosal-Associated Invariant T (MAIT) Cells Is Affected by Microbial Diversity and Riboflavin Utilization in vitro

“…We suggest that the MAIT cell activating potential of individual species, but also microbial communities, depends on the availability of riboflavin in the culture medium and on the culture conditions, which together determine the need for riboflavin biosynthesis. In support of this, culture conditions have recently been identified to alter the MAIT cell activating potential of E. coli (Schmaler et al, 2018).…”

The Diverse Family of MR1-Restricted T Cells

“…Finally, how Ags of differing affinity influence MAIT cell effector function is also unclear. A recent study, however, showed that activation of MAIT cells with Ags of weak, intermediate, or high potency induce differential changes in surface marker expression (58). This is reminiscent of what has been described for NKT cells in that TCR-mediated signaling events of different strength are capable of activating distinct transcriptional pathways and effector functions (54).…”

“…For example, exogenous IL-12/ 18 allows MAIT cells to produce IFN-g and respond to viral infections in the absence of TCR ligation (28,29), whereas MAIT cells in the liver (19) and female genital tract (65) are primed to produce IL-17 and also IL-22 in the latter. Likewise, MAIT cells in the colon differ substantially from their blood counterparts, expressing activation markers and inhibitory receptors and express higher levels of T-bet and RORgt, licensing stronger proinflammatory responses, in particular production of IFN-g and TNF (58). These characteristics may also allow MAIT cells to promote autoimmunity (66) and cancer (31), where dysregulated expression of innate cytokines can elicit an undesired MAIT cell effector response even in the absence of defined MAIT cell Ag.…”

AfricanSalmonellaTyphimurium sequence type 313 lineage 2 evades MAIT cell recognition by overexpressing RibB

“…Mutations in key enzymes of the riboflavin biosynthetic pathway in both Gram positive and negative bacteria can abrogate MAIT cell activation [33], [52]. Different bacteria that possess the riboflavin biosynthetic pathway induce varying levels of MAIT stimulation [36], [37], possibly through the influences of the microenvironment on bacterial metabolism and antigen availability, or the known short half-life of the potent MAIT cell antigens, 5-OP-RU and 5-OE-RU [53]. The ability of MAIT cells to recognise and respond to several isolates of the same pathogen may also vary to reflect bacterial metabolic differences.…”

“…While many commensal and pathogenic bacteria possess the riboflavin biosynthetic pathway, the levels of resulting MAIT stimulation varies [36], [37], perhaps reflecting the influence of microenvironment on bacterial metabolism and antigen availability. The ability of MAIT cells to recognise and respond to several isolates of the same pathogen may also vary depending on metabolic differences between isolates [38].…”