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

Abstract

Recent research has demonstrated that MAIT cells are activated by individual bacterial or yeasts species that possess the riboflavin biosynthesis pathway. However, little is known about the MAIT cell activating potential of microbial communities and the contribution of individual community members. Here, we analyze the MAIT cell activating potential of a human intestinal model community (SIHUMIx) as well as intestinal microbiota after bioreactor cultivation. We determined the contribution of individual SIHUMIx community members to the MAIT cell activating potential and investigated whether microbial stress can influence their MAIT cell activating potential. The MAIT cell activating potential of SIHUMIx was directly related to the relative species abundances in the community. We therefore suggest an additive relationship between the species abundances and their MAIT cell activating potential. In diverse microbial communities, we found that a low MAIT cell activating potential was associated with high microbial diversity and a high level of riboflavin demand and vice versa. We suggest that microbial diversity might affect MAIT cell activation via riboflavin utilization within the community. Microbial acid stress significantly reduced the MAIT cell activating potential of SIHUMIx by impairing riboflavin availability through increasing the riboflavin demand. We show that MAIT cells can perceive microbial stress due to changes in riboflavin utilization and that riboflavin availability might also play a central role for the MAIT cell activating potential of diverse microbiota.

Emerging Role for MAIT Cells in Control of Antimicrobial Resistance

“…Various bacteria have developed strategies to evade MAIT cell recognition or effector function, including alteration of the riboflavin biosynthesis pathway [74], ability of certain microbial products to downregulate MR1 or interfere with its trafficking [75], production of virulence factors, including bacterial superantigens [36,76], and induction of immunosuppressive cytokines [18]. Additionally, the availability of external riboflavin sources, and adverse growing conditions for bacteria, can affect bacterial recognition by MAIT cells and subsequent antimicrobial effector function [7,77,78]. Therefore, whether MAIT cell antimicrobial activity is still effective against bacteria growing under different environmental conditions should be thoroughly assessed.…”

Pathophysiological Roles of Mucosal-Associated Invariant T Cells in the Context of Gut Microbiota-Liver Axis

“…In addition to being an essential part of the gut microflora, they have been detected in breast milk which indicates that it could be one mechanism of how they are established in the infant’s gut and play major roles in MAIT cell development and expansion since early in life [ 49 ]. In another similar study that analyzed individual strains of species commonly found in the gut, the MAIT cell activation potential was found to positively correlate with the capacity of riboflavin secretion into the media [ 50 ]. Bacteroides thetaiotaomicron, which secreted the highest amount of riboflavin, resulted in the highest MAIT cell activation followed by E.coli and Lactobacillus plantarum which also showed intermediate and lower secretions, respectively.…”

MAIT Cells in Barrier Tissues: Lessons from Immediate Neighbors

“…In reality we have communities of microbes and there is evidence that increased microbial diversity is associated with improved MAIT cell reconstitution after allogeneic hematopoietic stem cell transplantation (81). This could partly be through a reduction in their activation induced cell death as in vitro microbial diversity has been shown to reduce MAIT cell activation (131). Testing common intestinal commensals in vitro has demonstrated that MAIT cell activation correlates with net riboflavin secretion, with higher diversity resulting in predominant riboflavin uptake and thus lower presentation to MAIT cells (131).…”

“…This could partly be through a reduction in their activation induced cell death as in vitro microbial diversity has been shown to reduce MAIT cell activation (131). Testing common intestinal commensals in vitro has demonstrated that MAIT cell activation correlates with net riboflavin secretion, with higher diversity resulting in predominant riboflavin uptake and thus lower presentation to MAIT cells (131). This is supported by observations in apical periodontitis oral mucosa, where prominent riboflavinexpressing taxa correlate negatively with Va7.2-Ja33 and IL17A transcripts (132).…”

“…Microbial metabolism is also shaped by the tissue microenvironment and could tune MAIT cell activation. One mechanism is through availability of TCR ligands derived from riboflavin synthesis: heat stress in Streptococcus pneumoniae induces expression of the riboflavin operon (134); and acid stress increases purine and folate metabolism, as well riboflavin uptake (19,131). Bacterial co-culture conditions influence their capacity to activate human MAIT cells in vitro (19); hypoxia, simulating the low oxygen tension in colonic crypts, stationary growth phase and hypercarbia increase MAIT cell activation, whereas hypoglycemia, acetate and pyruvate inhibit bacterial control (19).…”