Alternative splicing of MR1 regulates antigen presentation to MAIT cells

Abstract

Mucosal Associated Invariant T (MAIT) cells can sense intracellular infection by a broad array of pathogens. These cells are activated upon encountering microbial antigen(s) displayed by MR1 on the surface of an infected cell. Human MR1 undergoes alternative splicing. The full-length isoform, MR1A, can activate MAIT cells, while the function of the isoforms, MR1B and MR1C, are incompletely understood. In this report, we sought to characterize the expression and function of these splice variants. Using a transcriptomic analysis in conjunction with qPCR, we find that that MR1A and MR1B transcripts are widely expressed. However only MR1A can present mycobacterial antigen to MAIT cells. Coexpression of MR1B with MR1A decreases MAIT cell activation following bacterial infection. Additionally, expression of MR1B prior to MR1A lowers total MR1A abundance, suggesting competition between MR1A and MR1B for either ligands or chaperones required for folding and/or trafficking. Finally, we evaluated CD4/CD8 double positive thymocytes expressing surface MR1. Here, we find that relative expression of MR1A/MR1B transcript is associated with the prevalence of MR1 + CD4/CD8 cells in the thymus. Our results suggest alternative splicing of MR1 represents a means of regulating MAIT activation in response to microbial ligand(s).

MR1 overexpression correlates with poor clinical prognosis in glioma patients

“…MR1 is a non-polymorphic MHC class I-like molecule encoded in human chromosome 1 with many similarities to canonical class I molecules, but with the added distinction of being located mainly in the endoplasmic reticulum and endosomal vesicles. 11 , 12 MR1 presents microbial-derived vitamin B metabolites to an innate T cell called mucosal-associated invariant T cells 13 , 14 resulting in their proliferation and secretion of pro-inflammatory cytokines to control infection. 3 However, the exact involvement of the MR1 in cancer immunology is unknown.…”

Delivery of loaded MR1 monomer results in efficient ligand exchange to host MR1 and subsequent MR1T cell activation

“…Thus, we tested whether endogenous MR1 was required. We incubated WT BEAS-2B cells, MR1 -/- BEAS-2B cells lacking all isoforms of MR1, and MR1 -/- BEAS-2B cells reconstituted with tetracycline-inducible MR1A [25, 26] with MR1/5-OP-RU monomer and used them as antigen presenting cells. As expected based on the results reported in Figure 1, we detected responses to WT BEAS-2B cells incubated with MR1/5-OP-RU monomers (Figure 3a, left).…”

“…BEAS-2B cells were obtained from the American Type Culture Collection (ATCC) and cultured as recommended. BEAS-2B MR1 -/- , BEAS-2B MR1 -/- : MR1A cell lines were described previously [25, 26]. The BEAS-2B cell line overexpressing GFP-tagged MR1A (BEAS-2B.MR1-GFP) was described previously [12].…”

Deaza-modification of MR1 ligands modulates recognition by MR1-restricted T cells

“…The bronchial epithelial cell line BEAS-2B (CRL-9609) was originally obtained from ATCC and was cultured in DMEM + 10% heat inactivated fetal bovine serum (FBS). The BEAS-2B:ΔMR1 cell line was derived by CRISPR/Cas9 disruption of the MR1 gene, and MR1 expression was reconstituted in these cells 42 . Wild-type BEAS-2B cells overexpressing MR1 fused to GFP were previously described 22 .…”