bims-maitce 2025-09-28 papers

Issue of 2025–09–28
three papers selected by
Andy E. Hogan, Maynooth University

J Inflamm Res. 2025 ;18 13139-13157

The Emerging Roles and Therapeutic Potential of Unconventional T Cells in Sepsis.

Shuaipeng Gu, Peidong Zhang, Cong Zhang, Tingxuan Tang, Teding Chang, Liming Dong, Wei Gao, Zhaohui Tang.

Sepsis represents a dynamic, dysregulated host immune response to infection in which unconventional T cells-γδ T cells, mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and double-negative T cells-actively shape the balance between early hyperinflammation and subsequent immune paralysis across time and tissues. These cells employ unique antigen recognition mechanisms to trigger rapid immune responses. γδ T cells facilitate early pathogen elimination and immune regulation, whereas MAIT cells detect microbial metabolites and modulate the systemic inflammation. NKT cells balance immune homeostasis through dual pro- and anti-inflammatory cytokine production. This review classifies these subsets and examines their sepsis-related functions alongside immunotherapies targeting them, such as cytokine manipulation, immunomodulators, and checkpoint inhibitors. Elucidating the precise mechanisms underlying sepsis could advance therapies that restore immune equilibrium and potentially improve clinical outcomes. Future studies should unravel the interactions between unconventional T cells and broader immune networks while translating the findings into practical treatments. Understanding the dynamic roles of these cells provides pathways for tailored interventions in sepsis management.

Keywords: double-negative t cells; immunotherapy; invariant natural killer t cells; mucosal-associated invariant t cells; sepsis; γδ T cells

DOI: https://doi.org/10.2147/JIR.S545532

Front Immunol. 2025 ;16 1638522

Simultaneous profiling of the blood and gut T and B cell repertoires in Crohn's disease and symptomatic controls illustrates tissue-specific alterations in the immune repertoire of individuals with Crohn's disease.

Aya K H Mahdy, Valentina Schöpfel, Gert Huppertz-Hauss, Gøri Perminow, Florian Tran, Corinna Bang, Johannes R Hov, May-Bente Bengtson, Petr Ricanek, Randi Opheim, Tone Bergene Aabrekk, Trond Espen Detlie, Vendel A Kristensen, Mathilde Poyet, Marte Lie Høivik, Andre Franke, Hesham ElAbd.

Introduction: Crohn's disease (CD) is a clinical subset of inflammatory bowel disease that is characterized by patchy transmural inflammation across the gastrointestinal tract. Although the exact etiology remains unknown, recent findings suggest that it is a complex multifactorial disease with contributions from the host genetics and environmental factors such as the microbiome. We have previously shown that the T cell repertoire of individuals with CD harbors a group of highly expanded T cells which hints toward an antigen-mediated pathology.
Methods: We simultaneously profiled the αβ and γδ T cell repertoire in addition to the B cell repertoire of both the blood and the colonic mucosa of 27 treatment-naïve individuals with CD and 27 age-matched symptomatic controls.
Results: Regardless of disease status, we observed multiple physiological differences between the immune repertoire of blood and colonic mucosa. Additionally, by comparing the repertoire of individuals with CD relative to controls, we observed different alterations that were only detected in the blood or colonic mucosa. These include a depletion of mucosal-associated invariant T (MAIT) cells and an expansion of TRAV29/DV5-TRAJ5 + clonotypes in the blood repertoire of individuals with CD. Also, a significant depletion of multiple IGHV3-33-IGHJ4+ and IGHV3-33-IGHJ6+ clonotypes in the blood and gut IGH repertoire of individuals with CD.
Discussion: Our findings highlight the importance of studying the immune repertoire in a tissue-specific manner and the need to profile the T and B cell immune repertoire of gut tissues as not all disease-induced alterations will be detected in the blood.

Keywords: B cell repertoire; IBD - inflammatory bowel disease; T cell repertoire; blood immune repertoire; colon immune repertoire; immune repertoire analysis

DOI: https://doi.org/10.3389/fimmu.2025.1638522

Cancer Discov. 2025 Sep 25.

Microbial metabolic pathways guide response to immune checkpoint blockade therapy.

Studies have identified a link between specific microbiome-derived bacteria and immune checkpoint blockade (ICB) efficacy. However, these species lack consistency across studies and their immunomodulatory mechanisms remain elusive. To understand the influence of the microbiome on ICB response we studied its functional capacity. Using pan-cancer metagenomics data of ICB-treated patients, we showed that community-level metabolic pathways are stable across individuals, making them suitable to predict ICB response. We identified several microbial metabolic processes significantly associated with response, including the methylerythritol phosphate (MEP) pathway, which was associated with response and induced Vδ2 T cell-mediated anti-tumor responses in patient-derived tumor organoids. In contrast, riboflavin synthesis was associated with ICB resistance, and its intermediates induced mucosal-associated invariant T (MAIT) cell-mediated immune suppression. Moreover, gut metabolomics revealed that high riboflavin levels were linked to worse survival in patients with abundant intratumoral MAIT cells. Collectively, our results highlight the relevance of metabolite-mediated microbiome-immune cell crosstalk.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1669