bims-maitce 2026-09-20 papers

Issue of 2026–09–20
five papers selected by
Andy E. Hogan, Maynooth University

mBio. 2026 Sep 17. e0066326

MAIT cell responses to Staphylococcus aureus and sensitivity to HlgAB toxin are modulated by activation and tissue-dependent virulence effects.

Mucosa-associated invariant T (MAIT) cells are unconventional T cells with innate-like rapid antimicrobial effector functions and serve as resident sentinels at mucosal and non-mucosal barriers. However, their role in immune defense against Staphylococcus aureus and the impact of bacterial immune evasion mechanisms are incompletely understood. Here, we have investigated MAIT cell responses to S. aureus and the impact of its broadly expressed leukocidin toxin HlgAB on MAIT cell responses in different human tissue sites. MAIT cells respond to S. aureus with a complex polyfunctional profile spanning proinflammatory IL-17, TNF, and IFNγ, anti-inflammatory IL-10, plus granzymes A, B, and K, perforin, and granulysin. The quality of responses was influenced by the microbial dose and time of exposure and was dependent on both MR1-presented antigen and cytokine co-activation. CD56+ MAIT cells displayed stronger effector responses and higher HlgAB sensitivity compared to CD56⁻ cells. MAIT cells were partially resistant to HlgAB-toxicity compared to monocytes; blood-derived MAIT cells remained susceptible, whereas tonsillar MAIT cells showed minimal sensitivity. Notably, activation reduced the MAIT cell susceptibility to HlgAB, and such activation also afforded indirect protection to monocytes in co-cultures. The reduced susceptibility of tonsillar MAIT cells correlated with lower CCR2 and CXCR1 expression, a pattern shared with barrier tissues such as the lung and intestines. In conclusion, these findings indicate that MAIT cells exhibit tissue- and context-dependent responses to S. aureus and sensitivity to HlgAB-mediated immune evasion.
IMPORTANCE: Mucosa-associated invariant T (MAIT) cells are an evolutionarily conserved unconventional T cell subset that responds to riboflavin pathway-derived antigens from a range of microbes. Here, we found that the human MAIT cell response to the pathogen S. aureus is robust with the polyfunctional complexity influenced by bacterial concentration and response kinetics. The ubiquitously expressed S. aureus immune-evasive toxin HlgAB attacks MAIT cells via CCR2. However, the sensitivity of MAIT cells to HlgAB varies depending on tissue localization, where in particular tissue-resident MAIT cells in tonsils are resistant. Antigen-specific activation of MAIT cells reduces HlgAB sensitivity, with protection also afforded to monocytes in the vicinity. These findings uncover the complex and dynamic interaction between an evolutionarily conserved arm of immunity and immune evasion mechanisms of the important pathogen S. aureus.

Keywords: MAIT cells; MR1; Staphylococcus aureus; bacterial toxins; immune evasion; immunity; tissue-resident T cells

DOI: https://doi.org/10.1128/mbio.00663-26

MedComm (2020). 2026 Oct;7(10): e70996

Mucosal-Associated Invariant T Cells in Health and Disease.

Yu Zhao, Feng-Mi Ou, Dan Liang, Yang Gao, Qing-Qing Li, Yi-Qun Kuang.

Mucosal-associated invariant T (MAIT) cells are a population of evolutionarily conserved, unconventional innate-like T lymphocytes that are restricted by major histocompatibility complex Class I-related (MR1) molecules. They can be activated either in a T-cell receptor-MR1- or cytokine-dependent manner. Activated MAIT cells play crucial roles in maintaining homeostasis and the fine regulation of the immune system. This review presents a systematic exploration of the development, biological characteristics, and multiple effects of MAIT cells in health and various diseases. In healthy individuals, MAIT cells maintain mucosal barrier integrity, participate in tissue repair after injury, and prevent excessive inflammation. In microbial infections, MAIT cells eliminate infected cells and modulate immune responses or become pathogenic when overactivated by superantigens. In the context of immune-related diseases, MAIT cells migrate to inflamed tissues and become pathogenic by secreting tissue-damaging cytokines or protective by modulating immune responses. Moreover, MAIT cells have been demonstrated to have therapeutic applications in controlling diseases through their use as cellular adjuvants, their increased activation by engineered bacteria, and their modification with chimeric antigen receptors. This review synthesizes the functional plasticity of MAIT cells in health and disease, highlighting the therapeutic efficacy and limitations of engineered MAIT cells for precise intervention.

Keywords: MAIT cells; MR1; homeostasis maintenance; infectious and immune diseases; therapeutic application

DOI: https://doi.org/10.1002/mco2.70996

Front Immunol. 2026 ;17 1894779

Comprehensive immune profiling of human peripheral blood mononuclear cells using two complementary spectral flow cytometry panels encompassing 60 unique markers.

Maartje H Rietdijk, Leo C Kuhnen, Marlous van den Braber, Alberta G A Paul, M Fernanda Pascutti, Juan J García-Vallejo.

Comprehensive immune profiling is essential for immunomonitoring studies aimed at identification of diagnostic and prognostic biomarkers. Peripheral blood mononuclear cells (PBMCs) undergo phenotypic and functional changes during disease, making them invaluable for the characterization of immune cell composition in both cross-sectional and longitudinal immune monitoring studies. We have developed a comprehensive immunophenotyping method based on two complementary panels of 60 unique markers to characterize B cells, T cells, innate lymphoid cells (ILCs), γδ T cells, mucosal-associated invariant T (MAIT) cells, natural killer (NK) cells, monocytes, dendritic cells (DCs) and several of their subsets, including their functional status, within human peripheral blood mononuclear cells (PBMCs). Dividing the markers over two complementary panels allows for inclusion of many more markers than currently allowed for single panels by state-of-the-art spectral flow cytometers, enabling the immunophenotyping of a broad spectrum of immune cell subsets at great analytical depth. This includes rare subsets and subsets that require an extensive combination of markers to be resolved, combined with the option of assessing differentiation, activation and exhaustion. The method enables the resolution of more than 50 distinct populations, and detailed exploration of differentiation, activation and exhaustion of these subsets, as is demonstrated here on PBMC samples from healthy donors, glioblastoma, inflammatory bowel disease and COVID-19 patients. The protocol supports both manual and unsupervised data analysis approaches and is suitable for large-scale immunomonitoring studies requiring standardized, reproducible multi-batch workflows.

Keywords: PBMC; high dimensional data analysis; human; immunomonitoring; spectral flow cytometer

DOI: https://doi.org/10.3389/fimmu.2026.1894779

bioRxiv. 2026 Aug 05. pii: 2026.08.04.742562. [Epub ahead of print]

Loss of riboflavin biosynthesis leads to accumulation of select aromatic amino acids and loss of infectivity in Mycobacterium tuberculosis.

Neetika Jaisinghani, Arshia Arasappan, Atul Pradhan, Rimanpreet Kaur, Kelin Li, Jeffrey Aubé, Justin R Cross, Ruben J Jesus Faustino Ramos, Travis Hartman, Mary L Previti, Charles K Vorkas, Jessica C Seeliger.

Riboflavin biosynthesis is required for in vitro survival of the human pathogen Mycobacterium tuberculosis ( Mtb ). However, despite the lack of a known transporter, growth can be rescued by exogenous riboflavin. The riboflavin biosynthesis pathway is also predicted essential in vivo , but whether riboflavin levels available in the host can support survival has not been directly tested. Here we constructed a set of inducible CRISPR interference (CRISPRi) knockdown and targeted gene deletion strains for known riboflavin biosynthesis genes ( ribA2, ribG, ribH, ribC ) as tools to characterize riboflavin requirements, uptake, and metabolite changes and to assess in vivo essentiality. We found that riboflavin, but not flavin adenine dinucleotide or flavin mononucleotide, rescued auxotrophy for all strains tested. Further, riboflavin uptake did not show strong evidence of being dependent on active or facilitated transport, supporting the mechanism of passive diffusion. Targeted metabolite profiling after removal of riboflavin from growth medium confirmed reduced riboflavin levels. While other riboflavin intermediates were not detected, significant accumulation of aromatic amino acids (Phe, Tyr) was observed across all assayed strains, as well as alteration in a vitamin B9 metabolite. Selecting the ribC knockout as a representative strain, we found that riboflavin depletion had a bacteriostatic effect as late as 3 weeks after removal. Unexpectedly, Δ ribC lacked infectivity in an aerosol mouse infection, suggesting that the potential to scavenge riboflavin from the host is not sufficient to survive in vivo . Overall, our results show that altered metabolism upon loss of riboflavin biosynthesis leads to compromised Mtb infectivity.
IMPORTANCE: Tuberculosis remains one of the world's most deadly infectious diseases, underscoring the need to explore new drug targets. Riboflavin (vitamin B2) biosynthesis has emerged as a promising target because Mycobacterium tuberculosis ( Mtb ) depends on this pathway for survival. The riboflavin pathway also produces metabolites that modulate host mucosal-associated invariant T (MAIT) cell activity, towards understanding potential strategies for host-directed therapies. Here we found that disrupting riboflavin biosynthesis led to not only compromised survival, but also widespread changes to metabolism and loss of the ability to establish infection in an animal model. These findings improve our understanding of how Mtb adapts to metabolic stress, with implications for developing drugs that target riboflavin biosynthesis and for alterations in host immunity to be explored in future studies.

DOI: https://doi.org/10.64898/2026.08.04.742562

Inflamm Res. 2026 Sep 14. pii: 214. [Epub ahead of print]75(1):

Single-cell RNA profiling suggests goflikicept-mediated immune modulation in idiopathic recurrent pericarditis.

A Golovkin, E Markelova, E V Ignatieva, O Kalinina, O A Ivanova, D Antonets, Y Medvedeva, A Minin, D Shtokalo, V Ramensky, I Kudryavtsev, O Moiseeva, V Myachikova, Y Vyatkin, Y Lavrovsky, M Samsonov, A Maslyanskiy, A Kostareva, E Shlyakhto.

OBJECTIVE: Idiopathic recurrent pericarditis (IRP) is a rare autoinflammatory disorder characterized by NLRP3 inflammasome overactivation, resulting in excessive IL-1β and IL-1α production. Although IL-1 blockade shows promise as a therapeutic strategy, the underlying molecular mechanisms remain incompletely understood. We investigated the effect of goflikicept, a novel heterodimeric fusion protein that inhibits both IL-1β and IL-1α, on peripheral blood mononuclear cell (PBMC) transcriptomes from patients with IRP.
METHODS: Single‑cell RNA sequencing was performed on PBMCs from patients with IRP before and during goflikicept treatment. Treatment‑related transcriptomic signatures were analyzed across innate and adaptive immune cell subsets.
RESULTS: Goflikicept induced temporal transcriptional reprogramming, with a particularly pronounced downregulation of IL-1-related inflammatory pathways in classical monocytes by day 35 of treatment. Furthermore, goflikicept was associated with coordinated transcriptional changes in adaptive immune compartments, including naïve B cells, circulating plasma cell precursors, and unconventional T cell subsets (γδ T and MAIT cells).
CONCLUSIONS: Goflikicept effectively normalized dysregulated immune responses in IRP, supporting the broader therapeutic potential of IL-1 blockade in NLRP3-mediated inflammatory diseases. This study provides the first single-cell resolution insights into the molecular mechanisms of IL-1 blockade, informing the development of targeted therapies for autoinflammatory conditions.

Keywords: Goflikicept; IL-1 inhibiting; Idiopathic recurrent pericarditis; Single-cell RNA profiling

DOI: https://doi.org/10.1007/s00011-026-02347-x