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Here, we explore the relationship between dietary fibers, colonic epithelium major histocompatibility complex class II (MHC-II) expression, and immune cell interactions in regulating susceptibility to Clostridioides difficile infection (CDI). We find that a low-fiber diet increases MHC-II expression in the colonic epithelium, which, in turn, worsens CDI by promoting the development of pathogenic CD4 + intraepithelial lymphocytes (IELs). The influence of dietary fibers on MHC-II expression is mediated by its metabolic product, acetate, and its receptor, free fatty acid receptor 2 (FFAR2). While acetate activation of FFAR2 on epithelial cells helps resist CDI, it does not directly regulate MHC-II expression. Instead, MHC-II is regulated by FFAR2 in type 3 innate lymphoid cells (ILC3s). Acetate enhances interleukin-22 (IL-22) production by ILC3s, which then suppresses MHC-II expression on the colonic epithelium. In conclusion, a low-fiber diet reduces acetate-induced IL-22 production by ILC3s, leading to increased MHC-II on the colonic epithelium. This change affects recovery from CDI by expanding the population of pathogenic CD4 + IELs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

The upper oesophagogastrointestinal (UEGI) tract histology, intestinal morphometry and lymphocyte subpopulations of healthy people is scarcely known. In research studies of inflammation involving the UEGI tract, there is a lack of adequate healthy controls. Aims: To evaluate the histology of the UEGI tract and the duodenal lymphocyte subpopulations of healthy volunteers and patients with gastroesophageal reflux disease (GERD), the latter to assess if it could replace healthy subjects. Healthy individuals were excluded if they had symptoms, comorbidities, pregnancy, toxics, medications or abnormal blood analysis. Subjects in both groups with abnormal duodenal intraepithelial lymphocyte (IEL) counts were also excluded. A total of 280 subjects were assessed, and 37 were included (23 healthy and 14 with GERD). The GERD group showed a higher IEL count (median [IQR]: 19.5 [17-22]), than healthy group: (15 [12-18]), p = 0.004. Eosinophils, mast cells and intestinal morphometry were similar in both groups. In the lamina propria, CD4+ T cells decreased ( p = 0.008), and CD8+ T cells increased ( p = 0.014). The total innate lymphoid cells (ILC) and CD3- cells decreased ( p = 0.007) in GERD group compared to healthy controls. At the intraepithelial level, NKT cells increased ( p = 0.036) and ILC3 decreased ( p = 0.049) in the GERD group. This is the first study to comprehensively map the histology, morphometry and duodenal subpopulations of healthy volunteers to help define a "gold standard" of normality. The differences found between both groups suggest that, whenever possible, healthy subjects should be included in research studies. Alternatively, we can consider a well-defined homogenous group with GERD to serve as the control group.

Purpose: Conjunctival-resident γδT cells, the predominant ocular source of interleukin-17A (IL-17A), play crucial roles in dry eye disease (DED) pathogenesis. The upstream regulators of these cells are unknown. This study evaluated the role of conjunctival IL-23 expression in mediating γδT cell generation and elucidated its contribution to dry eye inflammatory responses., Methods: Single-cell RNA sequencing (scRNA-seq) was used to identify and quantify conjunctival mRNA molecules in γδT cells in mice. The IL-23 level increased in wild-type (WT) and decreased in γδT-deficient (TCRδ-/-) mice after dry eye was induced via an intelligently controlled environmental system (ICES). Flow cytometry and transcriptome sequencing were used to investigate the impact of the changes in IL-23 expression on human γδT cells., Results: The expression of the IL-23 receptor (IL-23R) was greater in γδT cells than in other conjunctival cell types, such as CD4+ T cells, CD8+ T cells and epithelial cells. An increase in IL-23 led to an increase in γδT cell density, which was proportional to dry eye severity. However, in the TCRδ-/- mice, the upregulation of IL-23 failed to increase the expression level of IL-17A and the severity of dry eye. Furthermore, increases in the expression of IL-23 and the number of γδT cells were evident in the ocular surface cells of patients who developed visual display terminal syndrome., Conclusions: An increase in conjunctival IL-23 expression contributes to the induction of the DED inflammatory response through interactions with its cognate receptor on γδT cells and the promotion of their proliferation. The findings of this study suggest that the suppression of IL-17A through the blockade of IL-23R activation may be a viable target for improving the management of inflammation in DED patients.

Aims: Diagnosis of coeliac disease (CD) with mild mucosal changes is difficult for all parties involved. We aimed to determine the power of T cell receptor (TCR)γδ + intra-epithelial lymphocytes (IELs) in discriminating CD from other causes of intra-epithelial lymphocytosis using a new monoclonal antibody., Methods: A total of 167 cases categorised as coeliac (117 untreated CD, classified according to Marsh, updated by Ensari, including 29 type 1, 29 type 2, 39 type 3 and 20 treated CD), and non-coeliac groups (24 controls and 26 non-coeliac IELosis) based on clinical, serological and histological data were studied for IEL counts enumerated per 100 enterocytes using haematoxylin and eosin, CD3, TCR δ-stains., Results: TCRγδ + IELs were significantly higher in CD (24.83 ± 16.13) compared to non-CD (6.72 ± 6.32) and were correlated with the degree of mucosal damage. Both γδ + IEL count and ratio showed higher performance in differentiating untreated coeliacs from controls, with a sensitivity of 83.76; 85.57 and specificity of 95.83; 79.17, respectively. TCRγδ + IEL counts distinguished type 1 CD (20.41 ± 13.57) from non-coeliac IELosis (9.42 ± 7.28) (p = 0.025). Discriminant analysis revealed that villus/crypt ratio, γδ + and CD3 + IEL counts, γδ + /CD3 + IEL ratio, IEL distribution pattern were potent discriminants and correctly classified 82.3% of cases while the algorithm accurately diagnosed 93.4% of cases., Conclusions: The new antibody detecting γδ + IELs in FFPE sections revealed thresholds of 10.5 for γδ + IELs and 14% for γδ + /CD3 + IEL ratio which distinguished coeliacs from non-coeliacs with high sensitivity and specificity, particularly in cases with normal villus/crypt axis including type 1 CD, non-CD IELosis and controls. A 'coeliac algorithm' based on γδ + IELs is proposed with the hope that it will be used in the histopathological diagnostic approach by the pathology community., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Intraepithelial type 1 innate lymphoid cells (ieILC1s) are tissue-resident lymphocytes in the microenvironment of head and neck squamous cell carcinoma. Here, we evaluate how these cells influence T-cell trafficking to tumors. We generated cytotoxic ieILC1-like cells from natural killer (NK) cells in vitro. Using an in vivo tumor model, we show that intratumoral ieILC1-like NK cells induce greater T cell trafficking into the tumor. Co-culture of ieILC1-like NK cells with the tumor cells resulted in elevated CXCL10 in the supernatant. Flow cytometry demonstrated that ieILC1-like NK cells produce robust amounts of IFNy, a known CXCL10 inducer, while CXCL10 was produced by tumor cells. These results indicate ieILC1-like NK cells induce tumor production of CXCL10, a proinflammatory chemokine that promotes T cell infiltration into the TME. The role of ieILC1-like NK cells in modulating clinical responses to immune checkpoint blockade warrants investigation., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Cetaceans exhibit remarkable wound healing capabilities. However, the specific immune mechanisms underlying this process, particularly the role of γδ T cells, remains largely unexplored. In ruminants, pigs, and camelids, which are members of the order Cetartiodactyla alongside cetaceans, γδ T cells express a unique receptor called workshop cluster 1 (WC1). Despite cetaceans also belonging to this order, the presence of WC1 in their γδ T cells has not yet been reported. This study aims to investigate the distribution and potential function of γδ T cells in cetacean skin during homeostasis and wound healing. Using immunofluorescence and immunohistochemical staining, we identified γδ TCR + and WC1 + cells in dolphin skin for the first time. These cells are predominantly located in the dermis and blubber, with an increased presence in healing wounds, suggesting their involvement in wound healing rather than pathogen defense. Furthermore, our findings revealed that γδ TCR + cells constitute a small fraction of CD3 + MHCII + cells in dolphin skin, indicating their intricate role in cetacean immunology. Additionally, the appearance of WC1 + cells in cetaceans highlights unique immunological features within Cetartiodactyla. Comparative analysis demonstrates that γδ T cells in dolphins exhibit distinctive morphological and distributional characteristics compared to those in humans, mice, and ruminants, implying species-specific adaptations. These insights contribute to a deeper understanding of cetacean immunology and underscore the potential evolutionary adaptations that support their exceptional wound healing capabilities. Future research on the genomic and functional aspects of γδ T cells in cetaceans is essential to further elucidate their roles in immune response and wound healing., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

New HIV vaccine approaches are focused on eliciting broadly neutralizing antibodies. We characterized early gamma-delta (γδ) T cell responses starting from pre-acquisition and during acute HIV infection (AHI) in participants previously characterized for neutralization breadth development. We found significant differences in γδ T cell surface marker expression in participants that developed neutralization breadth compared to those that did not. Activation of γδ T cells occurred within the first weeks of HIV acquisition and associated with viral load. Expression of CD16 on Vδ1 T cells and CD57 on Vδ2 T cells were found to be significantly higher in broad neutralizers during AHI, and associated with the development of neutralization breadth years later. In addition, the levels of CD16 on Vδ1 T cells was associated with early production of founder virus Env-specific IgM. Thus, γδ T cells may promote development of neutralization breadth, which has implications for HIV vaccine strategies., Competing Interests: The authors declare no competing interests., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: The small intestine harbors a rich array of intestinal intraepithelial lymphocytes (IELs) that interact with structural cells to collectively sustain gut immune homeostasis. Dysregulation of gut immune homeostasis was implicated in the pathogenesis of multiple autoimmune diseases, however, whether this homeostasis is disrupted in a lupus autoimmune background remains unclear., Methods: We performed single-cell RNA sequencing (scRNA-seq) analyses to elucidate immune and structural milieu in the intestinal epithelium of MRL/Lpr lupus mice (Lpr mice) and MRL/Mpj control mice (Mpj mice). Comprehensive analyses including unsupervised clustering, trajectories, and cellular communication were performed. The primary findings from scRNA-seq were further validated by quantitative polymerase chain reaction (qPCR), flow cytometry, and in vivo experiments including selenium supplementation., Results: We observed a significant reduction in CD8αα + IELs, accompanied by a marked increase in CD8αβ + IELs in Lpr mice. Additionally, subsets of CD8 + IELs exhibiting significantly enhanced effector functions were found to be markedly enriched in Lpr mice. Intercellular communication patterns within intestinal epithelial immune and structural cells were found to be specifically altered in Lpr mice. Moreover, scRNA-seq revealed significantly decreased intestinal TCRγδ T cells (γδT) associated with reduced aryl-hydrocarbon receptor repressor (AHRR) expression and subsequent oxidative stress and ferroptosis in Lpr mice. Antioxidant selenium effectively reversed the loss of γδT in Lpr mice, improved the gut barrier, and alleviated lupus symptoms., Conclusions: Our high-resolution single-cell atlas enhances the understanding of the immune and structural milieu of intestinal epithelium in lupus and provides new insights into lupus pathogenesis mediated by intestinal immune dysregulation., Competing Interests: Declarations. Ethics approval and consent to participate: All experiments adhered to the animal ethical and care guidelines established by the Institute of Dermatology, Chinese Academy of Medical Sciences (2023-DW-031). The research did not use any materials of human subjects. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

Background: γδT cells have been implicated in the pathogenesis of autoimmune diseases. The study aims to investigate the abundance of γδT cells in MRL/lpr mice., Methods: MRL/lpr mice were used as lupus models, while C3H/HeJ mice served as normal controls. The abundance of γδT cells in different organs was examined by flow cytometry. Plasma double-stranded DNA antibody levels, blood urea nitrogen, creatinine, and urinary protein levels were measured. Renal histopathology was observed via H&E staining. The correlations between the abundance of γδT cells and lupus manifestations were analyzed., Results: Compared with C3H/HeJ mice, the number of γδT cells and Vγ6 + γδT cell subset in the peripheral blood of MRL/lpr mice was significantly reduced. However, in the kidney, the number of γδT cells and Vγ6 + γδT cell subset was significantly increased. Additionally, the number of Vγ6 + γδT cells in the kidney was positively correlated with the urinary protein level. The number of IFN-γ + Vγ6 + γδT cells in the kidney was positively correlated with urinary protein level., Conclusion: In MRL/lpr mice, it is likely that peripheral γδT cells, especially the Vγ6 subset, infiltrate the kidney and secrete IFN-γ, which contributes to the development of lupus nephritis., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Human gammadelta (γδ) T cells not only infiltrate or reside in healthy tissues but also enter solid cancers. A large body of evidence suggests that γδ T cells can exert potent anti-tumor effects, although conflicting or unfavorable effects have been reported in some cancer entities. Infiltration patterns are key to understanding the complexity of the tumor microenvironment (TME) and its interplay with γδ T cells. The limited data available describe different γδ T cell subsets that are located in different areas around and within tumors. Tumor-infiltrating γδ lymphocytes (γδ TIL) exert cytotoxicity, for example, via the CD95- or TRAIL-axis, produce high amounts of granzymes, and after their activation, tumor necrosis factor (TNF)-α or IFN-γ and express immune checkpoint receptors. Under certain conditions, γδ T cell subsets can express low amounts of IL-17 and seem to contribute to immune regulation/suppression. A polarization of γδ T cells can be influenced by the TME. Inflammatory cytokines, growth factors, or tumor promoters can suppress γδ T cell functionality or even push them toward tumor promotion. To avoid this and to exploit the unique features of γδ T cell-mediated anti-cancer and immune-orchestrating capabilities in future immune therapy approaches, a growing body of preclinical but also clinical studies can be observed., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)