Fig. 7: Potential mechanism of MAIT cell contribution to inflammasome activation in vaccine-induced memory responses*. | Nature Communications

Fig. 7: Potential mechanism of MAIT cell contribution to inflammasome activation in vaccine-induced memory responses*.

From: Distinct gene expression signatures comparing latent tuberculosis infection with different routes of Bacillus Calmette-Guérin vaccination

Fig. 7

To explore potential mechanisms behind observed differential inflammasome responses, CompBio performed a genome-wide search for genes expressed in unstimulated BAL cells that correlated with the BAL Δ inflammasome profile scores of each participant. Significantly-correlated biological themes (a, top) included “recycling/trafficking endosomes” and “MAIT cells”. The associated heatmap displays baseline expression of ten genes associated with MAIT and endosome themes (a, bottom). Baseline expression of these genes was most robust in recipients of PO ± ID BCG, consistent with the greater Mtb-induced inflammasome profiles observed in these individuals (Fig. 6). Baseline BAL cell expression of MR1 and GABARPL2, two genes known to be important for optimal MAIT cell responses, displayed significant correlation with the inflammasome profile across all study groups (b, left); expression of these genes was significantly higher in recipients of PO ± ID BCG than in any other study groups, as shown in 7b, right (*p < 0.05, **p < 0.01 by two-tailed Mann-Whitney test; bar graphs display mean values and SD). Again, n = 6 controls, 10 LTBI individuals, 8 recipients of ID BCG, and 8 recipients of PO ± ID BCG. These findings suggest a potential mechanism in which MAIT cells provide a hypothetical link between baseline findings observed most strongly in recipients of PO ± ID BCG and subsequent inflammasome activation, c In steps illustrated from left to right, we hypothesize that PO ± ID BCG primes alveolar macrophages for MAIT activation through increased baseline expression of GABARAPL2 and the MR1 restriction molecule (step 1); these ready the APC for subsequent Mtb exposure, resulting in xenophagy that exposes Mtb-derived riboflavin metabolites and transports these to the endoplasmic reticulum to associate with MR1(step 2). MR1 endosomes then mediate transport of riboflavin /MR1 complexes to the cell surface for recognition by MAIT cells (step 3). Resulting activation of airway MAIT is suggested by Mtb-induced increases in DPP4 (CD26) (also step 3). MAIT activation then triggers observed downstream inflammation including IL17R, CD44 and GZMB gene expression and release of TNF protein (step 4). MAIT-derived TNF may then prime NRLP3 inflammasomes, providing a connection between vaccine-induced APC conditioning and Mtb-induced upregulation of inflammasome-associated genes NLRP3, CASP1, CASP5, IL6, CXCL2, and CXCL8 (step 5). *Fig. 7c: Bacterial cell images adapted from “E. coli, without flagella and pili” by BioRender.com (2023), retrieved from https://app.biorender.com/biorender-templates.

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