Biology subjects

Mathis, D.

Publications and source records attributed to Mathis, D..

10 recordsLinked to original sources

bioRxiv2025

Decoding Peripheral Tolerance: TCR Rules for pTreg differentiation in the Gut

Peripheral differentiation of regulatory T cells (pTregs) promoted by foreign antigens encountered in barrier tissues is considered a unique contributor to immunological tolerance to obligate non-self, like food or symbiotic microbes. The relative importance of adaptive recognition via the T cell receptor (TCR) vs environmental small-molecule or neuroimmune cues, is poorly understood. We leverage CRISPR-based TCR editing to perform in primary T cells in vivo, with a large panel of TCRs, a screen to assess pTreg differentiation induced by self, microbial, or dietary antigens. All antigen classes drive pTreg differentiation, which varies with the origin of the TCR: TCRs derived from Tregs enable pTreg differentiation much more effectively than those from Tconv. TCRs recognizing self, microbial, or dietary antigens elicit distinct pTreg phenotypes, Helios, ROR{gamma}, or both. Mechanistically, these trace to different types of antigen-presenting-cell involved. That Treg-derived TCRs preferentially drive tolerogenic fate speaks to preferential drivers of tolerogenic therapy.

immunology↗

bioRxiv2024

Expansion of mammary intraepithelial lymphocytes and intestinal inputs shape T cell dynamics in lactogenesis

Pregnancy brings about profound changes in the mammary gland to prepare for lactation, yet immunocyte changes that accompany this rapid remodeling are incompletely understood. We comprehensively analyzed mammary T cells, revealing a marked increase in CD4+ and CD8+ T effector cells, including an expansion of TCR{beta}+CD8+ cells, in pregnancy and lactation. T cells were localized in the mammary epithelium, resembling intraepithelial lymphocytes (IELs) typically found in mucosal tissues. Similarity to mucosal tissues was substantiated by demonstrating partial dependence on microbial cues, T cell migration from the intestine to the mammary gland in late pregnancy, and shared TCR clonotypes between intestinal and mammary tissues, including intriguing public TCR families. Putative counterparts of mammary IELs were found in human breast and milk. Mammary T cells are thus poised to manage the transition from a non-mucosal tissue to a mucosal barrier during lactogenesis.

immunology↗

bioRxiv2024

The meninges host a unique compartment of regulatory T cells that bulwarks adult hippocampal neurogenesis

Our knowledge about the meningeal immune system has recently burgeoned, particularly our understanding of how innate and adaptive effector cells are mobilized to meet brain challenges. However, information on how meningeal immunocytes guard brain homeostasis in healthy individuals remains sparse. This study highlights the heterogeneous and polyfunctional regulatory-T (Treg) cell compartment in the meninges. A Treg subtype specialized in controlling Th1-cell responses and another known to control responses in B-cell follicles were substantial components of this compartment, foretelling that punctual Treg-cell ablation rapidly unleashed interferon-gamma production by meningeal lymphocytes, unlocked their access to the brain parenchyma, and altered meningeal B-cell profiles. Distally, the hippocampus assumed a reactive state, with morphological and transcriptional changes in multiple glial-cell types; within the dentate gyrus, neural stem cells showed exacerbated death and desisted from further differentiation, associated with inhibition of spatial-reference memory. Thus, meningeal Treg cells are a multifaceted bulwark to brain homeostasis at steady-state. One sentence summaryA distinct population of regulatory T cells in the murine meninges safeguards homeostasis by keeping local interferon-{gamma}-producing lymphocytes in check, thereby preventing their invasion of the parenchyma, activation of hippocampal glial cells, death of neural stem cells, and memory decay.

immunology↗

bioRxiv2023

An interwoven network of transcription factors, with divergent influences from FoxP3, underlies Treg diversity

FoxP3+CD4+ regulatory T cells (Tregs), essential for immunologic and organismal homeostasis, have diverse functions and corresponding gene expression programs. How the many controlling transcription factors (TFs) organize to determine Treg identity and diversity remains unclear. We combined single-cell chromatin accessibility profiling, machine learning, and high-density natural genetic variation, validated with TF knockout, CRISPR-editing, and binding data, to define the Treg regulatory network. Distal enhancers proved driven by imbricated multi-TF inputs, employing strategies different from promoter regions. Topic modelling resolved a framework of chromatin programs shaped by distinct TF motifs. This framework anchored surprisingly heterogenous responses to IL2. It identified an unrecognized role for the Smarcc1 remodeler. FoxP3 impacted only some segments of this framework, either activating or repressing programs, amplifying a core Treg identity defined independently. Its absence in Treg-like cells unleashed cytokine expression, but not Th de-differentiation. This work provides a unifying scaffold to understand and manipulate Treg states.

immunology↗

bioRxiv2023

Homeostatic, repertoire and transcriptional relationships between colon T regulatory cell subsets

Foxp3+ regulatory T cells (Tregs) in the colon are key to promoting peaceful co-existence with symbiotic microbes. Differentiated in either thymic or peripheral locations, and modulated by microbes and other cellular influencers, colonic Treg subsets have been identified through key transcription factors (TF; Helios, Rorg, Gata3, cMaf), but their inter-relationships are unclear. Applying a multimodal array of immunologic, genomic, and microbiological assays, we find more overlap than expected between populations. The key TFs play different roles, some essential for subset identity, others driving functional gene signatures. Functional divergence was clearest under challenge. Single-cell genomics revealed a spectrum of phenotypes between the Helios+ and Ror{gamma}+ poles, different Treg-inducing bacteria inducing the same Treg phenotypes to varying degrees, not distinct populations. TCR clonotypes in monocolonized mice revealed that Helios+ and Ror{gamma}+ Tregs are related, and cannot be uniquely equated to tTreg and pTreg. We propose that rather than the origin of their differentiation, tissue-specific cues dictate the spectrum of colonic Treg phenotypes.

immunology↗

bioRxiv2022

A dynamic atlas of immunocyte migration from the gut

Dysbiosis in the gut microbiota impacts several systemic diseases. One possible mechanism is the migration of perturbed intestinal immunocytes to extra-intestinal tissues. Combining the Kaede photoconvertible mouse model and single-cell genomics, we generated a detailed map of migratory trajectories from the colon, at baseline and during intestinal and extra-intestinal inflammation. All colonic lineages emigrated from the colon in an S1P-dependent manner, dominated by B lymphocytes with a large continuous circulation of follicular B cells, which carried a gut-imprinted transcriptomic signature. T cell emigration was more selective, with distinct groups of ROR{gamma}+ or IEL-like CD160+ cells in the spleen. Gut inflammation curtailed emigration, except for DCs disseminating to lymph nodes. Colon emigrating cells distributed differentially to tumor, skin inflammation, or arthritic synovium, the former dominated by myeloid cells in a chemokine-dependent manner. These results thus reveal specific cellular trails originating in the gut, influenced by microbiota, which can shape peripheral immunity.

immunology↗

bioRxiv2021

FoxP3 associates with enhancer-promoter loopsto regulate Treg-specific gene expression

Gene expression programs are specified by higher-order chromatin structure and enhancer-promoter loops (EPL). T regulatory cells (Treg) identity is dominantly specified by the transcription factor FoxP3, whose mechanism of action is unclear. We applied proximity-ligation with chromatin immunoprecipitation (HiChIP) in Treg and closely related conventional CD4+ T cells (Tconv). EPL identified by H3K27Ac HiChIP showed a range of connection intensity, with some super-connected genes. TF-specific HiChIP showed that FoxP3 interacts with EPLs at a large number of genes, including some not differentially expressed in Treg vs Tconv, but enriched at the core Treg signature loci that it upregulates. FoxP3 association correlates with heightened H3H27Ac looping, as ascertained by analysis of FoxP3-deficient Treg-like cells. There was marked asymmetry in the loci where FoxP3 associated at the enhancer- or the promoter-side of EPLs, with enrichment for different transcriptional cofactors. FoxP3 EPL intensity distinguished gene clusters identified by single-cell ATAC-seq as co-varying between individual Tregs, supporting a direct transactivation model for FoxP3 in determining Treg identity. One Sentence SummaryFoxP3 is associated with enhancer-promoter loops in Treg cells, and correlates with heightened enhancer-promoter cross-talk

immunology↗

bioRxiv2020

Profound Treg perturbations correlate with COVID-19 severity

The hallmark of severe COVID-19 disease has been an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We explored the hypothesis that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in both Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, which correlated with poor outcomes. Accordingly, these Tregs over-expressed a range of suppressive effectors, but also pro-inflammatory molecules like IL32. Most strikingly, they acquired similarity to tumor-infiltrating Tregs, known to suppress local anti-tumor responses. These traits were most marked in acute patients with severe disease, but persisted somewhat in convalescent patients. These results suggest that Tregs may play nefarious roles in COVID-19, via suppressing anti-viral T cell responses during the severe phase of the disease, and/or via a direct pro-inflammatory role.

immunology↗

bioRxiv2020

Single cell analysis of FOXP3 deficiencies in humans and mice unmasks intrinsic and extrinsic CD4+ T cell perturbations

ABSTRACTFOXP3 deficiency in humans with IPEX syndrome and mice results in fatal systemic autoimmunity by altering regulatory T cell (Treg) physiology, but actual cellular and molecular mechanisms of disease are unclear, part because Treg surface markers may be unreliable in disease states. We used deep profiling by flow cytometry, population and single-cell RNAseq to analyze Tregs and conventional (Tconv) CD4+ T lymphocytes in cohorts of IPEX patients with a range of genetic lesions, and in Foxp3-deficient mice. In all patients and mice, heterogeneous Treg-like cells with an active FOXP3 locus were observed, some differing very little from normal Tregs, others more distant. Tconv showed no widespread activation or Th bias. The dominant mark was a monomorphic signature equally affecting all CD4+ T cells, unexpectedly dampening tumor-Treg and cytokine-signaling modules. In mixed bone marrow chimeras, WT Tregs exerted dominant suppression, normalizing the states of mutant Treg and Tconv, extinguishing the disease signature, and revealing a small gene cluster truly regulated, cell-intrinsically, by FOXP3. These results suggest a two-step pathogenesis model, with therapeutic implications: limited downregulation of a few core Treg genes de-represses a systemic mediator(s), which imprints the disease signature on all T cells, and further dampens Treg function.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2020

Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance

Aggregate-like biomolecular assemblies are emerging as new conformational states with functionality. Aire, a transcription factor essential for central T cell tolerance, is known to form large aggregate-like assemblies visualized as nuclear foci. We demonstrate that Aire utilizes Caspase Activation Recruitment Domain (CARD) to form filamentous homo-multimers in vitro, and this assembly mediates foci formation and transcriptional activity. However, CARD-mediated multimerization is a double-edged sword as it also makes Aire susceptible to interaction with PML bodies, sites of many nuclear processes including protein quality control of nuclear aggregates. Several loss-of-function Aire mutants, including those causing autoimmune polyendocrine syndrome type-1, form foci with increased PML body association. Directing Aire to PML bodies impairs Aires transcriptional activity, while dispersing PML bodies with a viral antagonist restores it. Thus, our study reveals a new regulatory role of PML bodies in Aire function and highlights the interplay between nuclear aggregate-like assemblies and PML-mediated quality control.

immunology↗