bims-maitce 2025-06-08 papers

Issue of 2025–06–08
three papers selected by
Andy E. Hogan, Maynooth University

Lupus. 2025 Jun 05. 9612033251348151

Esculentoside A alleviates lupus nephritis by modulating MAIT cells in MRL/lpr mice.

Xing Wang, Xiaoxue Weng, Xianghui Zhang, Ting Zhao, Xianggui Zhang, Jieyin Tang.

IntroductionThis study aims to investigate the protective effect of esculentoside A (EsA) on lupus nephritis (LN) by modulating the mucosal-associated invariant T (MAIT) cells and associated cytokines in the renal tissue of MRL/lpr mice.MethodsEighteen 16-week-old female MRL/lpr mice were randomly assigned into the model and EsA groups (9 mice each), and 9 age-matched female Balb/c mice were included as a normal group. Mice were administered 0.2 mL of EsA solution (2.5 mg/mL) or RPMI 1640 medium (for control groups) via intraperitoneal injection once daily for 4 weeks. Urine protein/creatinine ratio (URCR) and blood creatinine (Cr) concentration were measured, Hematoxylin-eosin and Masson staining of renal tissues were performed, and the "Austin" acute index (AI) system for LN was determined and the protein expression of TNF-α, IFN-γ, IL-2, and IL-17 were assessed by Western blot. The proportion of MAIT cells in kidney tissues was analyzed using flow cytometry. Pearson correlation analysis was performed between renal MAIT cells and the expression of TNF-α, IFN-γ, IL-2, and IL-17 proteins in kidney tissues. Data were analyzed with SPSS 26.0 software.ResultsCompared with the normal group, the model group exhibited significantly elevated levels of Cr, UCPR, renal expression of TNF-α, IFN-γ, and IL-17, as well as an increased proportion of MAIT cells, along with the most severe renal histopathological damage and the highest AI score. In contrast, the EsA group showed a notable reduction in these parameters, although they remained elevated compared to the normal group. Kidney IL-2 expression was significantly lower in the model group than in the normal group, while EsA treatment resulted in an increase in IL-2 levels. Renal MAIT cells were positively correlated with TNF-α, IFN-γ, and IL-17 expression but negatively correlated with IL-2.DiscussionEsA confers protection against LN in MRL/lpr mice by downregulating the proportion of MAIT cells in kidney tissue, reducing the expression of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-17), and increasing IL-2 expression.

Keywords: Mucosal-associated invariant T cells; esculentoside A; interleukin-17; interleukin-2; lupus nephritis; tumor necrosis factor

DOI: https://doi.org/10.1177/09612033251348151

J Autoimmun. 2025 Jun 02. pii: S0896-8411(25)00087-3. [Epub ahead of print]154 103442

The phenotypic and functional characteristics of intrahepatic CD69+CD103+ tissue-resident MAIT cells in primary biliary cholangitis.

Qiyun Xia, Zhuwan Lyu, Yudong Zhao, Xiting Pu, Jian Wang, Yuyang Liu, Yujie Zhou, Jun Qian, M E Gershwin, Min Lian, Xiong Ma.

BACKGROUND & AIMS: Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset that plays a significant role in the immunopathology of primary biliary cholangitis (PBC). However, our understanding of the subpopulations involved in hepatic residency have not been elucidated. Herein, our goal was to delineate the phenotypic and functional properties of intrahepatic tissue-resident MAIT cells in PBC.
METHODS: Liver tissue and intrahepatic mononuclear cells were collected and analyzed by immunohistochemistry, immunofluorescence and flow cytometry. The transcriptome was determined using in vitro generated tissue-resident MAIT cells. FOXM1's immunoregulatory role was evaluated with inhibitor treatment and regulatory features of BHLHE40 were confirmed by CUT&Tag-seq and luciferase assays.
RESULTS: In PBC, the frequency of intrahepatic MAIT cell decreased, but tissue-resident (CD69+CD103+) MAIT cells significantly expanded and expressed a notably pro-inflammatory phenotype, with substantial elevated expression of CXCR3, CXCR6; IL-17A, IFN-γ and T-bet. FOXM1, a transcriptional factor governing cell proliferation cycle, exhibited notably higher expression in tissue-resident MAIT cells than in non-resident MAIT cells. Inhibition of FOXM1 compromised the in vitro expansion of MAIT cells, and impaired the expression of CXCR3, IL-17A, IFN-γ and GM-SCF by tissue-resident MAIT cells. CUT&Tag-seq and luciferase assay revealed a direct regulation of FOXM1 of BHLHE40 expression.
CONCLUSION: Our data reveals a pro-inflammatory role of expanded tissue-resident MAIT cells in PBC mediated via higher expression of effector cytokines, chemokine receptors and a related transcriptional factor. FOXM1 critically regulates MAIT cell proliferation and tissue-resident pro-inflammatory function, via interaction with BHLHE40, and establishes a transcriptional axis linking proliferation to effector responses.

Keywords: Inflammation; Liver microenvironment; Mucosal-associated invariant T cells (MAIT cells); Primary biliary cholangitis (PBC); Tissue-residency

DOI: https://doi.org/10.1016/j.jaut.2025.103442

bioRxiv. 2025 May 19. pii: 2025.05.14.654109. [Epub ahead of print]

Mutations outside the MR1 antigen binding groove differentially inhibit presentation of exogenous antigens.

Corinna A Kulicke, Chance Lemon, Jason R Krawic, Luisa Maria Nieto Ramirez, Se-Jin Kim, Gitanjali Narayanan, Fikadu G Tafesse, William H Hildebrand, Karen M Dobos, David M Lewinsohn.

The antigen presenting molecule MHC class I-related protein 1 (MR1) binds small molecule metabolites derived from microbial riboflavin biosynthetic pathways and presents them at the cell surface for surveillance by MR1-restricted mucosal-associated invariant T cells (MAIT cells). MR1 ligands can originate in the extracellular space or in endosomal compartments that contain microbial pathogens. Distinct, complementary antigen processing and presentation pathways enable MR1 to survey diverse intracellular locations and present both exogenous and intracellular antigens. Here, we generated a panel of BEAS-2B MR1 KO cells reconstituted with MR1 proteins mutated at amino acids 9 - 16. The mutated MR1 molecules differentially translocated to the cell surface in response to 6-formylpterin and differed in their ability to present mycobacterial antigens to MAIT cell clones. While they barely presented Mycobacterium smegmatis supernatant and other exogenous MAIT cell antigens, their ability to present antigens derived from mycobacterial infection and a 5-A-RU prodrug requiring endosomal processing remained largely intact. Protein co-immunoprecipitation and mass spectrometry-based proteomic analysis showed that mutated MR1 differentially associated with calnexin and β 2 -microglobulin (B2M). Knock-down of B2M in cells over-expressing MR1 phenocopied the loss of exogenous antigen presentation but did not impact presentation of intracellular antigens. Thus, the MR1-mediated presentation of exogenous antigen appears to be limited by binding to B2M whereas the lower sensitivity to B2M deficiency implies that MAIT cell activation via the endosomal antigen presentation pathway may be limited by the availability of MR1 itself.

DOI: https://doi.org/10.1101/2025.05.14.654109