Conserved γδ T cell selection by BTNL proteins limits progression of human inflammatory bowel disease

Dart, Robin J.; Zlatareva, Iva; Vantourout, Pierre; Theodoridis, Efstathios; Amar, Ariella; Kannambath, Shichina; East, Philip; Recaldin, Timothy; Mansfield, John C.; Lamb, Christopher A.; Parkes, Miles; Irving, Peter M.; Prescott, Natalie J.; Hayday, Adrian C.

doi:10.1126/science.adh0301

Cited by 24 publications

(3 citation statements)

References 81 publications

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“…We also found that the vast majority of mucosal CD4 -MAIT cells express CD103 (integrin αEβ7), which adheres to the E-cadherin molecule expressed by intestinal epithelial cells [76]. While IBD has been associated with a lower percentage of dendritic cells [77], CD8 and CD4 T cells [78] and γδ T cells [79] expressing CD103, we saw no such thing in MAIT cells (Fig 2D ), and by fluorescent intensity we actually found a higher per-cell expression of CD103 protein on the CD103+ MAIT cells of IBD biopsies, regardless of inflammation (Fig 2E). Although analyses of histological morphology were outside the scope of this study, the CD103 + phenotype of intestinal MAIT cells (Fig 2D ) and their relative depletion from de-epithelialized colon lamina propria preparations (Fig 2F) suggests that they are intra-epithelial lymphocytes (IEL), in close proximity to the intestinal lumen, and thus the gut microbiome.…”

Section: Plos Onementioning

confidence: 61%

Colonic mucosal associated invariant T cells in Crohn’s disease have a diverse and non-public T cell receptor beta chain repertoire

Konecny,

Shows,

Lord

2023

PLoS ONE

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Objectives Mucosal-Associated Invariant T (MAIT) cells are T cells with a semi-invariant T cell receptor (TCR), recognizing riboflavin precursors presented by a non-polymorphic MR1 molecule. As these precursors are produced by the gut microbiome, we characterized the frequency, phenotype and clonality of MAIT cells in human colons with and without Crohn’s disease (CD). Methods The transcriptome of MAIT cells sorted from blood and intestinal lamina propria cells from colectomy recipients were compared with other CD8+ T cells. Colon biopsies from an additional ten CD patients and ten healthy controls (HC) were analyzed by flow cytometry. TCR genes were sequenced from individual MAIT cells from these biopsies and compared with those of MAIT cells from autologous blood. Results MAIT cells in the blood and colon showed a transcriptome distinct from other CD8 T cells, with more expression of the IL-23 receptor. MAIT cells were enriched in the colons of CD patients, with less NKG2D in inflamed versus uninflamed segments. Regardless of disease, most MAIT cells expressed integrin α4β7 in the colon but not in the blood, where they were enriched for α4β7 expression. TCR sequencing revealed heterogeneity in the colon and blood, with few public sequences associated with cohorts. Conclusion MAIT cells are enriched in the colons of CD patients and disproportionately express molecules (IL-23R, integrin α4β7) targeted by CD therapeutics, to suggest a pathogenic role for them in CD. Public TCR sequences were neither common nor sufficiently restricted to a cohort to suggest protective or pathogenic antigen-specificities.

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Section: Plos Onementioning

confidence: 61%

Colonic mucosal associated invariant T cells in Crohn’s disease have a diverse and non-public T cell receptor beta chain repertoire

Konecny,

Shows,

Lord

2023

PLoS ONE

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“…Nonetheless, compared to Cy3 + HA − or Cy3 − HA − γδ T cells, Cy3 + HA + γδ T cells exhibited lower CD3ε and TCRδ expression levels ( Fig. 4 C ), which is indicative of prior antigenic exposure ( 57 ).…”

Section: Resultsmentioning

confidence: 97%

γδ T cell antigen receptor polyspecificity enables T cell responses to a broad range of immune challenges

Guo,

Chowdhury,

Mallajosyula

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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γδ T cells are essential for immune defense and modulating physiological processes. While they have the potential to recognize large numbers of antigens through somatic gene rearrangement, the antigens which trigger most γδ T cell response remain unidentified, and the role of antigen recognition in γδ T cell function is contentious. Here, we show that some γδ T cell receptors (TCRs) exhibit polyspecificity, recognizing multiple ligands of diverse molecular nature. These ligands include haptens, metabolites, neurotransmitters, posttranslational modifications, as well as peptides and proteins of microbial and host origin. Polyspecific γδ T cells are enriched among activated cells in naive mice and the responding population in infection. They express diverse TCR sequences, have different functional potentials, and include the innate-like γδ T cells, such as the major IL-17 responders in various pathological/physiological conditions. We demonstrate that encountering their antigenic microbiome metabolite maintains their homeostasis and functional response, indicating that their ability to recognize multiple ligands is essential for their function. Human γδ T cells with similar polyspecificity also respond to various immune challenges. This study demonstrates that polyspecificity is a prevalent feature of γδ T cell antigen recognition, which enables rapid and robust T cell responses to a wide range of challenges, highlighting a unique function of γδ T cells.

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“…Prior studies have shown that BTNL3 binds to Vg4+ T-cell receptors in a manner akin to superantigens 70 . Crucially, there is evidence that BTNL3’s role in selecting and maintaining γδ T cells is significant in curbing the progression of complex intestinal diseases that cause tissue damage 14 . This finding is particularly relevant, given that many of the common risk alleles associated with genetic predisposition to SLE are found in genes related to the immune system.…”

Section: Resultsmentioning

confidence: 99%

Group Heteroscedasticity - A Silent Saboteur of Power and False Discovery in RNA-Seq Differential Expression

Chatterjee,

Fadikar,

Hanumesh

et al. 2024

Preprint

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Despite the availability of several high-profile, state-of-the-art methods, analyzing bulk RNA-Seq data continues to face significant challenges. Evidence from recent studies has highlighted that popular differential expression (DE) tools, such as edgeR and DESeq2, are susceptible to an alarmingly high false discovery rate (FDR). These studies suggest that the FDR inflation observed in these models could be attributed to issues such as violations of parametric assumptions or an inability to effectively handle outliers in the data. Here, we argue that group heteroscedasticity can also contribute to this elevated FDR, a phenomenon largely overlooked by the research community. We introduce a novel statistical model, Robseq, designed for effective per-feature modeling in differential analysis, particularly when the assumption of group homoscedasticity is unmet. Robseq utilizes well-established statistical machinery from the robust statistics literature, including M-estimators to robustly estimate gene expression level changes and Huber-Cameron variance estimators to calculate robust standard errors in heteroscedastic settings. Additionally, it incorporates a degrees of freedom adjustment for the Welch t-statistic, based on Bell-McCaffrey's recommendation, for inferential purposes, effectively addressing the problem of FDR inflation in RNA-Seq differential expression. Through detailed simulations and comprehensive benchmarking, we show that Robseq successfully maintains the false discovery and type-I error rates at nominal levels while retaining high statistical power compared to well-known DE methods. Analysis of population-level RNA-Seq data further demonstrates that Robseq is capable of identifying biologically significant signals and pathways implicated in complex human diseases that otherwise cannot be revealed by published methods. The implementation of Robseq is publicly available as an R package at https://github.com/schatterjee30/Robseq.

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Conserved γδ T cell selection by BTNL proteins limits progression of human inflammatory bowel disease

Cited by 24 publications

References 81 publications

Colonic mucosal associated invariant T cells in Crohn’s disease have a diverse and non-public T cell receptor beta chain repertoire

Colonic mucosal associated invariant T cells in Crohn’s disease have a diverse and non-public T cell receptor beta chain repertoire

γδ T cell antigen receptor polyspecificity enables T cell responses to a broad range of immune challenges

Group Heteroscedasticity - A Silent Saboteur of Power and False Discovery in RNA-Seq Differential Expression

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