Biology subjects

Tchitchek, N.

Publications and source records attributed to Tchitchek, N..

8 recordsLinked to original sources

bioRxiv2026

A regulatory T cell signature provides a shared molecular basis for the therapeutic window of opportunity in rheumatic disease

Rheumatic diseases, including rheumatoid arthritis (RA), spondyloarthritis (SpA) and osteoarthritis (OA), show distinct phenotypes yet respond to overlapping therapies, implicating shared immune mechanisms. In the Transimmunom cohort, we profiled peripheral blood from 240 individuals (47 healthy, 44 OA, 91 RA, 58 SpA) across deep immunophenotyping, immunoproteomics and Treg-Teff transcriptomics. Single-layer analyses revealed broader Treg than Teff remodeling, along with a shared pattern of reduced activated Tregs and expanded Helios+ Tregs across all diseases, alongside a decrease in functional Treg subpopulations, including CTLA4+ and CD45RA- Tregs. In RA specifically, LAG3+ Tregs were also expanded. Combining omics layers outperformed single-layer approaches for disease classification. Among individual layers, Treg transcriptomes were most discriminative, and integration uncovered disease-specific programs. Unsupervised clustering identified a cross-disease cluster independent of activity, treatment and age, mapping to early disease (<= years) and dominated by a Treg dysfunction-associated program. These results provide a biological rationale for the therapeutic "window of opportunity" concept and duration-stratified Treg-directed trials.

immunology↗

bioRxiv2024

Immunological Profiling in Knee Osteoarthritis: Treg Dysfunction as Key Driver of Pain

Pain is the hallmark symptom of osteoarthritis (OA) and its biological drivers remain poorly understood. While the role of innate immunity in OA has been extensively studied, the involvement of adaptive immunity, in particular regulatory T cells (Tregs), is not well understood. Using a comprehensive multi-omic approach on the peripheral blood from 46 knee OA patients with similar radiographic stage, including deep immunophenotyping, cytokine profiling, transcriptomic and T-cell receptor analysis on sorted CD4 Tregs and effector T cells (Teff), we identified an immunological signature associated with OA-related pain. Cytokines promoting Treg expansion and activation (with increases of sIL2-RA, sTNFR1, sTNFR2) were correlated with the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscore, suggesting a potential Treg dysfunction. Nineteen T cell subsets were correlated with WOMAC pain. Notably, we found a negative correlation of cell subsets associated with Treg expansion and activation (FoxP3+CTLA4+, CD4+CD57+, Treg CD95+, CD4 Treg CD45RA-). Differential gene expression analysis between patients with low and high WOMAC pain intensity (threshold [≥] 40/100) revealed an upregulation of inflammasome-related genes such as IL1RL1, IL31RA, IFITM3, NLRP3, IFNG in Tregs. Functional enrichment analysis highlighted an overrepresentation of innate immune response, IL-8, and interferon activation pathways suggesting a pro-inflammatory state in Tregs of patients with high pain intensity. Collectively, our systems immunology approach highlights multiple associations between Treg dysfunctionality and OA-related pain, providing new insights into the adaptive immune systems contribution to OA-related pain.

immunology↗

bioRxiv2024

IL-1β Signaling Modulates T Follicular Helper and Regulatory Cells in Human Lymphoid Tissues

BackgroundDysregulation of the T follicular helper (Tfh) and T follicular regulatory (Tfr) homeostasis in the germinal center (GC) can result in antibody-mediated autoimmunity. While interleukin-1{beta} (IL-1{beta}) has been shown to be an important modulator of the GC response in animal models via the expression of IL-1 agonist (IL-1R1) and antagonist (IL-1R2) receptors on follicular T cells, such regulation has not yet been studied in humans. MethodsWe investigated Tfh and Tfr phenotypes in human secondary lymphoid organs -- namely tonsils, spleens, and mesenteric lymph nodes -- using flow cytometry, single-cell transcriptomics, and in vitro cell culture. We also benchmarked our findings with a cohort of patients with autoimmune and inflammatory diseases. ResultsWe found that Tfh and Tfr cells exhibit organ-specific phenotypes related to their activation status and IL-1 receptor expression. An excess of IL-1R1 over IL-1R2 was linked to the emergence of a unique activated Tfr subset that combines features of both Treg and GC-Tfh cells. Single-cell transcriptomics and in vitro studies showed that IL-1{beta} signaling through IL-1R1 promotes follicular T-cell activation. Inhibiting IL-1{beta} resulted in upregulation of IL-1R1 expression, showing a fine-tuned regulation. In autoimmune patients, high IL-1{beta} and circulating Tfr levels correlated with higher autoantibody levels, linking inflammation, IL-1{beta} signaling, and the Tfr/Tfh balance. ConclusionsOur study underscores the pivotal role of IL-1{beta} in follicular T-cell activation, contributing to pathological antibody production in humans. Targeting IL-1{beta} signaling in Tfh and Tfr cells could offer new treatment strategies for antibody-mediated autoimmune diseases.

immunology↗

bioRxiv2023

Tissue-resident uterine regulatory T cells support fetal growth

Regulatory T cells (Tregs) are known to contribute to successful allogeneic pregnancy by promoting maternal-fetal tolerance. Here, phenotypic studies and parabionts identified a population of uterine tissue-resident Tregs (uTregs) with trophic functions in the non-pregnant mouse endometrium. Phenotypically, uTregs are CD25-/lo and they present characteristic phenotypic attributes of tissue-resident memory T cells with effector functions. Transcriptionally, uTregs are distinguishable from other peripheral or tissue-resident Tregs by their expression of genes related to extracellular matrix remodeling and vasculogenesis, and they express a polyclonal T cell receptor (TCR) repertoire. Pregnancy triggers the expansion of uTregs, which remain CD25-/lo, retain their polyclonal TCR repertoire, and increase the expression of genes involved in regulation of hypoxia and vasculogenesis. Functionally, we show that uTregs support the proliferation of primary uterine microvascular endothelial cells in vitro and that a specific depletion of uTregs in pregnant mice leads to fetal intra-uterine growth retardation (IUGR). Thus, a previously unidentified population of CD25-/lo uTregs promotes uterine tissue remodeling before and during pregnancy, and contributes to fetal growth.

immunology↗

bioRxiv2021

The route of vaccine administration determines whether blood neutrophils undergo long-term phenotypic modifications

Innate immunity modulates adaptive immunity and defines the magnitude, quality, and longevity of antigen-specific T- and B- cell immune memory. Various vaccine and administration factors influence the immune response to vaccination, including the route of vaccine delivery. We studied the dynamics of innate cell responses in blood using a preclinical model of non-human primates immunized with a live attenuated vaccinia virus, Modified vaccinia virus Ankara (MVA), and mass cytometry. We previously showed that MVA induces a strong, early, and transient innate response, but also late phenotypic modifications of blood myeloid cells after two months when injected subcutaneously. Here, we show that the early innate effector cell responses and plasma inflammatory cytokine profiles differ between subcutaneous and intradermal vaccine injection. Additionally, we show that the intradermal administration fails to induce more highly activated/mature neutrophils long after immunization, in contrast to subcutaneous administration. Different batches of antibodies, staining protocols and generations of mass cytometers were used to generate the two datasets that were compared. Mass cytometry data were analyzed in parallel using the same analytical pipeline based on three successive clustering steps, including SPADE, and categorical heatmaps were compared using the Manhattan distance to measure the similarity between cell cluster phenotypes. Overall, we show that the vaccine per se is not sufficient for the late phenotypic modifications of innate myeloid cells, which are evocative of innate immune training. Its route of administration is also crucial, likely by influencing the early innate response, and systemic inflammation, and the vaccine biodistribution.

immunology↗

bioRxiv2020

Human USP18 is regulated by miRNAs via the 3'UTR, a sequence duplicated in lincRNA genes residing in chr22q11.21

Ubiquitin-specific peptidase 18 (USP18) acts as gatekeeper of type I interferon (IFN) responses by binding to the IFN receptor subunit IFNAR2 and preventing activation of the downstream JAK/STAT pathway. In any given cell type, the level of USP18 is a key determinant of the output of interferon-stimulated transcripts. How the baseline level of USP18 is finely tuned in different cell types remains ill defined. Here we explored post-transcriptional regulation of USP18 by microRNAs (miRNAs) and identified four miRNAs (miR-24-3p, miR-191-5p, miR-423-5p and miR-532-3p) that efficiently target USP18 through binding to the 3UTR. Among these, three miRNAs are particularly enriched in circulating monocytes which exhibit low baseline USP18. Intriguingly, the USP18 3UTR sequence is duplicated in human and chimpanzee genomes. In human, we found several copies of the 3UTR that are embedded in long intergenic non-coding (linc) RNA genes residing in chr22q11.21 and exhibiting a tissue-specific expression pattern. Interestingly, one of these lincRNAs (here named linc-UR-B1) is uniquely and highly expressed in testis. RNA-seq data analyses from testicular cell subsets revealed a positive correlation between linc-UR-B1 and USP18 expression in spermatocytes and spermatids. Overall, our findings uncover a set of miRNAs and lincRNAs, which may be part of a network evolved to fine-tune baseline USP18, particularly in cell types where IFN responsiveness needs to be tightly controlled. SIGNIFICANT STATEMENTUSP18 is a non-redundant negative feedback regulator of type I IFN signaling and a key determinant of cell responsiveness to IFN. How baseline USP18 is set in different human cell types is ill defined. We identified three microRNAs that restrain USP18 level notably in primary monocytes through binding the 3UTR. We found several copies of the USP18 3UTR embedded in long intergenic non-coding (linc) RNAs which reside in a complex region of human chromosome 22. These lincRNAs are expressed in a tissue-specific manner. We describe one lincRNA expressed only in testis, and most notably in germ cells. Correlative analyses suggest that microRNAs and lincRNAs may form a network controlling baseline USP18 and IFN responsiveness.

immunology↗

bioRxiv2019

Targeting MOG to skin macrophages prevents EAE in macaques through TGFβ-induced peripheral tolerance

To study the effect of vaccination on tolerization to the myelin antigen MOG we used a macaque model of experimental autoimmune encephalitis (EAE) in which immunization with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) elicits brain inflammation and demyelination mediated by MOG-specific autoreactive CD4+ T lymphocytes and anti-MOG IgG. For antigen targeting to tolerizing antigen presenting cells, we used a recombinant antibody directed to the Dendritic Cells (DC)-Asialoglycoprotein receptor (DC-ASGPR). The intradermal administration of an anti-DC-ASGPR-MOG fusion protein, but not a control anti-DC-ASGPR-PSA (prostate specific antigen) protein, protected monkeys committed to develop EAE. Although effective treatment did not modify anti-MOG IgG production, it prevented the CD4+ T lymphocyte activation and pro-inflammatory cytokine production. Moreover, animals treated with anti-DC-ASGPR-MOG experienced a rise of MOG-specific CD4+CD25+FOXP3+CD39+ regulatory T cells as well as a TGF{beta}1, TGF{beta}2 and IL-8 upsurge after rhMOG re-immunization. Our results indicate that the pathogenicity of autoantibodies directed to MOG is mitigated in the presence of MOG-specific regulatory lymphocytes. This vaccination scheme appears suitable to treat relapsing autoimmune diseases with identified autoantigens such as that harboring anti-MOG or anti-AQP4 autoantibodies.

immunology↗

bioRxiv2017

Stage-specific ISG expression reveals functional convergence of type I and II IFNs in SIV infection

AbstractInterferons play a major role in controlling viral infections including HIV/SIV infections. Persistent up-regulation of interferon-stimulated-genes (ISGs) is associated with chronic immune activation and progression in SIV/HIV infections, but the respective contribution of different IFNs is unclear. We analyzed the expression of annotated IFN-induced genes in SIV-infected macaques to decrypt the respective roles of type-I (,{beta}) and type-II ({gamma}) IFNs. Both IFN types were induced in lymph nodes during early stage of primary infection. Induction of type-II IFN persisted during the chronic phase, in contrast to undetectable induction of type-I IFN. Interferome-based analysis of ISGs revealed that at both acute and chronic infection phases most differentially expressed ISGs were inducible by both type-I and type-II IFNs and displayed the highest increases, indicating strong convergence and synergy between type-I and type-II IFNs. The analysis of functional signatures of ISG expression revealed temporal changes in IFN expression patterns identifying phase-specific ISGs. These results suggest that IFN-{gamma} strongly contribute to shape ISG upregulation in addition to type-I IFN and may contribute to progression.

immunology↗