bims-maitce 2026-03-29 papers

J Hepatocell Carcinoma. 2026 ;13 575861

Integrative Single-Cell and Spatial Transcriptomic Analysis Reveals MAIT Cell Dysfunction in Relapsed HCC.

Geon Woo Park, Hayoung Jang, Thuy Nguyen-Phuong, Hyunsung Nam, Chung-Gyu Park, Gwang Hyeon Choi, Sook-Hyang Jeong, Jin-Wook Kim, Chang Jin Yoon, Jae Hwan Lee, Hyun Je Kim.

Purpose: Hepatocellular carcinoma (HCC) frequently recurs after curative treatment, and the tumor immune microenvironment plays an important role in disease progression. However, the role of mucosal-associated invariant T (MAIT) cells in relapsed HCC remains poorly understood. This study aimed to characterize transcriptional and spatial features of MAIT cells in relapsed HCC and their association with malignant hepatocyte phenotypes.
Patients and Methods: Tumor samples from primary (n = 3) and relapsed (n = 2) HCC patients were analyzed using paired single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. scRNA-seq data (49,229 cells) were processed using Seurat with standard quality-control thresholds, followed by Harmony batch correction and unsupervised clustering. Malignant hepatocytes were identified by copy-number variation inference. Spatial transcriptomic data from 35 regions of interest were normalized and deconvolved using scRNA-seq-derived reference profiles. Independent validation was performed using a public HCC scRNA-seq dataset.1.
Results: Integrated analyses revealed distinct tumor microenvironmental features in relapsed HCC. Relapsed tumors showed increased representation of malignant hepatocytes with elevated cancer stemness-related transcriptional signatures compared with primary tumors (1.18-fold increase, p < 0.0001), which was spatially supported by enrichment in tumor regions (1.10-fold increase, p ≤ 0.05). Within the T/NK compartment, MAIT cells were significantly enriched in relapsed tumor regions (2.71-fold increase, p ≤ 0.05). Transcriptomic profiling identified distinct MAIT cell states between primary and relapsed HCC, with relapsed MAIT cells displaying dysfunctional phenotype. Cell-cell interaction analysis suggested enhanced ligand-receptor interactions between MAIT cells and malignant hepatocytes in relapsed tumors. In the TCGA LIHC cohort, high relapsed MAIT cell signature scores were associated with poorer overall survival (HR = 1.52, p ≤ 0.05).
Conclusion: Relapsed HCC is characterized by enhanced malignant hepatocyte stemness and altered MAIT cell states within the tumor microenvironment. These findings suggest an association between MAIT cell dysregulation and relapse-specific tumor biology, warranting further functional investigation.

Keywords: hepatocellular carcinoma; mucosal-associated invariant t cells; tumor microenvironment; tumor-infiltrating lymphocytes

DOI: https://doi.org/10.2147/JHC.S575861

bioRxiv. 2026 Mar 19. pii: 2026.03.17.712383. [Epub ahead of print]

MAIT cell responses to S. aureus and sensitivity to HlgAB 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 pro-inflammatory 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 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: 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 a 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 .

DOI: https://doi.org/10.64898/2026.03.17.712383

Genomics Proteomics Bioinformatics. 2026 Mar 21. pii: qzag027. [Epub ahead of print]

CD4+ T cells in Type 1 Diabetes: Inferring Stage-specific Dysregulation from scRNA-seq.

Deciphering the cellular and molecular mechanisms of type 1 diabetes (T1D) has long been a central goal in immunology. Here, we perform a large-scale single-cell transcriptomic analysis of peripheral blood mononuclear cells from children with T1D, their first-degree relatives, and healthy controls, enabling high-resolution profiling of immune dynamics across disease stages. We identify distinct immune signatures associated with pathogenesis: an expansion of non-mature regulatory T cells (Tregs) marks new-onset T1D, coinciding with clinical manifestation. During active autoimmunity, we observe increased Th22 cells linked to tumor necrosis factor (TNF) and interleukin (IL)-6 upregulation, reduced mucosal-associated invariant T (MAIT) cells with altered functional activity, and elevated ADAM10 and ADAM17 expression, promoting proinflammatory intercellular signaling. In contrast, the later phase of disease is characterized by Th17 cell accumulation and enhanced signalling through TGF-β1 and IL-12. Transcriptional regulatory network analysis highlights BACH2 as a key regulator of Treg maturation, implicating its dysregulation in immune tolerance breakdown. Dynamic shifts in CD4+ T cell subsets and cell-cell communication reveal stage-specific immunological trajectories. These findings provide a comprehensive map of systemic immune remodelling in T1D and uncover potential biomarkers and therapeutic targets for stage-stratified intervention.

Keywords: Autoimmune diseases; Gene network; Regulatory T cells; T helper cells; Transcriptional regulation

DOI: https://doi.org/10.1093/gpbjnl/qzag027

Front Immunol. 2026 ;17 1722621

Tuberculosis preventive therapy in postpartum women with HIV modifies M. tuberculosis-specific and nonspecific immune responses.

Damayanti Yengkhom, Grace Montepiedra, Gaerolwe Masheto, Deo Wabwire, Lynda Stranix-Chibanda, Allen Matubu, Avy Violari, Gerhard Theron, Amita Gupta, Adriana Weinberg.

Background: Tuberculosis (TB) has significant morbidity in pregnant and postpartum women with HIV (pregnant and PPWWHIV). TB preventive therapy (TPT) is recommended in pregnant and PPWWHIV with documented or presumed latent TB infection (LTBI). TB-stimulated IFNγ release assay and skin test positivity decline after TPT, but the underlying mechanisms and relationship with TB-specific immunologic memory are incompletely understood. We investigated this aspect in PPWWHIV.
Methods: PPWWHIV with LTBI received isoniazid TPT between 12 and 40 weeks postpartum. Blood obtained at 12 and 44 weeks postpartum was used to compare functional and phenotypic characteristics of unstimulated and TB-stimulated CD4+ and CD8+ conventional T cells (Tconv); unconventional T cells, including γδ, iNKT, MR1+ and MR1- MAIT, and NKT; NK; and antigen presenting cells (APC) pre- and post-TPT.
Results: In 45 participants with medians of 477 CD4+ T cells/µL and <50 HIV RNA copies/mL of plasma on antiretroviral therapy, both Tconv and innate immune cells responded to TB antigenic stimulation in vitro with an increase in functional markers. TPT was associated with a pronounced decrease in the proportions of granzyme B-expressing Tconv and unconventional T cell subsets both in TB-stimulated and unstimulated conditions. TB-stimulated Th1- and Th17-like responses in unconventional T cells also decreased from pre- to post-TPT. TB-stimulated conventional and unconventional regulatory T cells mostly decreased after TPT with a few exceptions. Very few changes were observed in circulating or TB-stimulated APC in response to TPT.
Conclusions: TPT was associated with a significant decrease in TB-specific T cell responses, including Tconv but mostly unconventional T cells, suggesting an important role of unconventional T cell memory in the control of TB infection. The prominent decrease of granzyme B-expressing T cells in response to TPT highlighted the importance of granzyme B in the maintenance of LTBI.

Keywords: HIV; granzyme B; immunologic memory; innate cell immunologic memory; interferon γ; isoniazid; pregnancy; preventive therapy

DOI: https://doi.org/10.3389/fimmu.2026.1722621