bims-maitce 2025-03-30 papers

Issue of 2025–03–30
three papers selected by
Andy E. Hogan, Maynooth University

Circ Res. 2025 Mar 26.

MAIT Cells Promote Cholesterol Excretion Pathways Mitigating Atherosclerosis.

Hua Wang, Pukar K C, Kaidi Zhang, Clément Materne, Marie Lhomme, Sophie Galier, Farid Ichou, Carolina Neves, Agnes Lehuen, Joel T Haas, Joe-Elie Salem, Maryse Guerin, Philippe Lesnik.

BACKGROUND: Previous clinical studies have indicated reduced circulating mucosal-associated invariant T (MAIT) cells in individuals with coronary artery disease. However, the precise role and underlying mechanisms of MAIT cells in this context remain unclear. Immune homeostasis plays a pivotal role in the development of atherosclerosis. This study explores the impact of MAIT cells on atherosclerosis.
METHODS: Vα19+/- Ldlr-/- mice, characterized by a high MAIT cell frequency, and MAIT cell deficient MR1-/- (major histocompatibility complex-related molecule 1) Ldlr-/- mice and their respective controls were used. Starting at 6 weeks of age, mice were subjected to a 1% cholesterol diet for 16 weeks. Additionally, the study analyzed circulating MAIT cell frequency and cholesterol levels in 68 patients with hypercholesterolemia.
RESULTS: In Vα19+/- Ldlr-/- mice, increased MAIT cells demonstrated a protective effect against atherosclerosis by reducing VLDL-C (very-low-density lipoprotein cholesterol) levels through heightened cholesterol excretion. This effect was accompanied by elevated jejunal ABCB1a, ABCG5, and ABCG8 expression, mediated by augmented levels of LXR transcription and activation, likely through intestinal IL-22 (interleukin-22) signaling. Conversely, cholesterol reduction mediated by intestinal cholesterol excretion was blocked by inhibition of MAIT cells. Moreover, MAIT cell-deficient MR1-/- Ldlr-/- mice exhibited elevated total cholesterol levels and increased atherosclerotic lesions. In patients with hypercholesterolemia, circulating MAIT cell frequency displayed negative correlations with VLDL-C levels and positive correlations with HDL-C (high-density lipoprotein cholesterol) levels.
CONCLUSIONS: Our findings demonstrate a new mechanism for plasma VLDL-C clearance by MAIT cell-mediated cholesterol excretion. The results provide further evidence that immunity is involved in cholesterol homeostasis. Targeting intestinal immunity to regulate cholesterol homeostasis holds promise as a new cholesterol-lowering modality to prevent atherosclerotic cardiovascular disease.

Keywords: atherosclerosis; cholesterol, dietary; coronary artery disease; hypercholesterolemia; mucosal-associated invariant T cells

DOI: https://doi.org/10.1161/CIRCRESAHA.124.325841

mBio. 2025 Mar 26. e0388724

Herpes simplex virus type 1 impairs mucosal-associated invariant T cells.

Lauren Stern, Zoe Emanuel, Renee Traves, Katherine Willis, Shivam K Purohit, Carolyn Samer, Jeffrey Y W Mak, David P Fairlie, David C Tscharke, Alexandra J Corbett, Allison Abendroth, Barry Slobedman.

Herpes simplex virus type 1 (HSV-1) is a highly successful pathogen that infects mucosal sites and adopts an arsenal of strategies to manipulate host immunity. Mucosal-associated invariant T (MAIT) cells are abundant innate-like T lymphocytes that recognize bacterial and fungal-derived vitamin B-related metabolites presented by major histocompatibility complex class I-related protein 1 (MR1). MAIT cells can also be activated in an MR1-independent manner via cytokine stimulation, predominantly by IL-12 and IL-18. MAIT cell alterations have been identified as being associated with a number of viral infections, but direct interactions between viruses and MAIT cells are poorly understood. It is unknown whether HSV-1 can infect MAIT cells and modulate their functions. Here, we show that HSV-1 can infect primary human MAIT cells, including CD4±/CD8± and CD56± MAIT cell subpopulations. Furthermore, HSV-1 infection profoundly inhibits the functional capacity of MAIT cells to respond to T cell receptor (TCR)-dependent stimulation by the MAIT cell activating ligand 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) and to cytokine stimulation by IL-12/IL-18. HSV-1-infected MAIT cells display reduced cytotoxic potential, diminished synthesis of effector cytokines, and decreased expression of key cytokine receptors including IL-18R. In addition, MAIT cells exposed to HSV-1-infected fibroblasts but which remained uninfected (viral GFP-negative) also exhibit a suppressed effector response to TCR-dependent stimulation. The functional suppression of HSV-1-exposed MAIT cells was not mediated by a soluble factor within the supernatant, suggesting direct contact of MAIT cells with HSV-1-infected fibroblasts is required. Overall, this study reveals that HSV-1 can infect MAIT cells and substantially impair MAIT cell effector functions.
IMPORTANCE: Mucosal-associated invariant T cells (MAIT cells) are "unconventional" immune cells that are becoming increasingly appreciated to play important roles in a variety of viral infections. Herpes simplex virus (HSV) causes significant human disease and is a master manipulator of multiple immune functions, but how this virus may control MAIT cells is poorly understood. We discovered that HSV can infect human MAIT cells and impair their functional capacity and also show that MAIT cells exposed to HSV, but which do not show evidence of infection, are similarly impaired. This study therefore identifies an additional immunomodulatory function of HSV.

Keywords: HSV; HSV-1; MAIT cell; herpes simplex virus; herpesvirus; immune modulation; mucosal-associated invariant T cell

DOI: https://doi.org/10.1128/mbio.03887-24

Clin Transl Immunology. 2025 ;14(3): e70029

Mucosal-associated invariant T cells correlate with myocardial ischaemia and remodelling in coronary artery disease.

Jiafu Wang, Song Li, Xianling Zhou, Hongxing Wu, Xiaolan Ouyang, Zhuoshan Huang, Long Peng, Qian Chen, Yuman Wu, Zhitong Li, Ziyi Peng, Yi Yang, Yan Lu, Xixiang Tang, Yue Li, Suhua Li.

Objectives: Myocardial ischaemia and remodelling are major contributors to the progression and mortality of coronary artery disease (CAD). Previous studies have shown immune cell alterations in CAD patients, but their characteristics and associations with myocardial ischaemia and remodelling remain unclear.
Methods: We compared immune cell changes among patients without CAD, those with CAD and those with CAD and heart failure (HF).
Results: We found a progressive reduction in circulating mucosal-associated invariant T (MAIT) cells across the three patient groups. MAIT cells exhibited increased expression of activation markers (CD69 and PD-1) and cytotoxic molecules (such as granzyme B). The features of MAIT cells were correlated positively with worsening clinical indicators of myocardial ischaemia and remodelling, including the Gensini score, cTnI, NT-proBNP, LVEF and E/e'. Additionally, the reduction, activation and cytotoxicity of MAIT cells were associated with indicators of myocardial fibrosis (sST2, Gal-3, PICP and PIIINP), a central pathological mechanism of myocardial remodelling. Finally, we preliminarily explored potential triggers for MAIT cell abnormalities in CAD patients and found that impaired intestinal barrier function and increased circulating bacterial antigens may contribute to these changes.
Conclusions: During CAD progression, we observed a decrease in circulating MAIT cells. Enhanced activation and cytotoxicity of MAIT cells are associated with myocardial ischaemia and remodelling in CAD patients with heart failure, potentially triggered by gut microbial leakage. Our findings suggest a novel strategy for monitoring and intervention in disease progression.

Keywords: MAIT cells; coronary artery disease; gut barrier permeability; heart failure; myocardial fibrosis

DOI: https://doi.org/10.1002/cti2.70029