Regulatory T cells epigenetically reprogrammed from autoreactive effector T cells mitigate established autoimmunity
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ABSTRACT:
PROVIDER: PRJNA1297086 | ENA |
REPOSITORIES: ENA
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Project description:Reprogramming autoreactive CD4⁺ effector T (Teff) cells into immunosuppressive regulatory T (Treg) cells represents a promising strategy for treating established autoimmune diseases. However, the stability and function of such reprogrammed Tregs under inflammatory conditions remain unclear. Here, we show that demethylation of core Treg identity genes in Teff cells yields lineage-stable Effector T cell Reprogrammed Tregs (ER-Tregs). A single adoptive transfer of ER-Tregs not only prevents autoimmune neuroinflammation in mice when given before disease onset but also arrests its progression when administered after onset. Compared to Foxp3‑overexpressing Teff cells, induced Tregs from naïve precursors, and endogenous Tregs, ER‑Tregs provide superior protection against autoimmune neuroinflammation. This enhanced efficacy stems from their inherited autoantigen specificity and selectively preserved effector‑cell transcriptional programs, which together bolster their fitness in inflammatory environments and enhance their suppressive capacity. Our results establish epigenetic reprogramming of autoreactive Teff cells as an effective approach to generate potent, stable Tregs for the treatment of refractory autoimmune conditions.
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Project description:The aim of the experiment is to identify candidate genes to phenotype epitope-specific autoreactive B cells. These genes could serve as markers to delineate further populations of autoreactive B cells that were shown to be key players in regulating autoimmunity and in explaining B cell selection.
2023-08-31 | E-MTAB-13291 | biostudies-arrayexpress
Project description:Transcriptional profiling of mouse bone marrow B220+CD23–CD43–IgD– autoreactive immature B cells from 3-83Igi,Rag1-/-,H-2b mice relative to non-autoreactive immature B cells from 3-83Igi,H-2d mice. Goal was to determine genes that potentially mediate negative and positive selection of immature B cells. Biological replicates: 2 autoreactive replicate against, 2 non-autoreactive replicates
2010-08-31 | E-GEOD-22802 | biostudies-arrayexpress
Project description:Presentation of tissue-restricted antigens (TRA) in the thymus is essentialfor establishing self-tolerancethrough elimination of autoreactive Tcells.It remains unclear why certain self T cells can bypassthymic selectionand become driversoftissue-specific autoimmunity. Herewe assessedthymic TRA presented by a major histocompatibility class II molecule (MHC-II) that confers genetic propensity to develop type 1 diabetes. This analysisestablished the thymic peptidome containing self-peptidesderivedfrom variousperipheral tissues,butalso revealed a disparity in the MHC-II epitoperepertoirebetween thymus and the target site of autoimmunity, the pancreatic islets.The thymic repertoire consistedof canonicalMHC-IIepitopes capable of enforcing central tolerance but lacked presentation of uniqueepitopes derived from unconventionalself-proteinprocessing orneoepitopes formed by post-translational modifications. Suchepitopes were noteworthily generatedin the isletsvia a tissue-intrinsic mechanism, crinophagy, and were recognized by CD4 T cells escaping central tolerance.These findings supportthat central tolerance mechanisms are effective but incomplete, as tissue-characteristic handling of self-antigens may broaden the peripheralrepertoire thatextends beyond the scope of thymic selection.
2024-08-22 | PXD030999 | Pride
Project description:Most autoreactive B cells are normally counterselected during early B cell development. To determine whether Toll-like receptors (TLRs) regulate the removal of autoreactive B lymphocytes, we tested the reactivity of recombinant antibodies from single B cells isolated from patients deficient for IL-1R-associated kinase (IRAK)-4, myeloid differentiation factor 88 (MyD88) and UNC-93B. Indeed, all TLRs except TLR3 require IRAK-4 and MyD88 to signal and UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8 and TLR9. All patients suffered from defective central and peripheral B cell tolerance checkpoints resulting in the accumulation of large numbers of autoreactive mature naïve B cells in their blood. Hence, TLR7, TLR8, and TLR9 may prevent the recruitment of developing autoreactive B cells in healthy donors. Paradoxically, IRAK-4-, MyD88- and UNC-93B-deficient patients did not display autoreactive antibodies in their serum nor developed autoimmune diseases, suggesting that IRAK-4, MyD88 and UNC-93B pathway blockade may thwart autoimmunity in humans.
2008-10-23 | GSE13300 | GEO
Project description:Transcriptional profiling of mouse bone marrow B220+CD23–CD43–IgD– autoreactive immature B cells from 3-83Igi,Rag1-/-,H-2b mice relative to non-autoreactive immature B cells from 3-83Igi,H-2d mice. Goal was to determine genes that potentially mediate negative and positive selection of immature B cells.
2010-08-31 | GSE22802 | GEO
Project description:Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene segregates with most autoimmune diseases; its risk allele encodes overactive PTPN22 phosphatases that alter B cell receptor (BCR) signaling potentially involved in the regulation of central B cell tolerance. To assess whether PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s). We found that new emigrant/transitional and mature naive B cells from PTPN22 risk allele carriers contained high frequencies of autoreactive clones compared to non-carrier control donors. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection, suggesting that early B cell tolerance checkpoint defects precede the onset of autoimmunity. In addition, gene array experiments comparing mature naïve B cells from healthy individuals carrying or not PTPN22 risk allele(s) revealed that the strength of association of PTPN22 for autoimmunity, second in importance only to the MHC, may not only be due to BCR signaling alteration but also to the regulation of other genes, which themselves have also been identified as involved in the development of autoimmune diseases. The PTPN22 risk allele is a single nucleotide change (cytidine to thymidine) at residue 1858, which results in a single amino acid substitution from arginine to tryptophan at position 620 of the PTPN22/Lyp protein.
2010-10-16 | GSE24736 | GEO
Project description:Complement receptor 2–negative (CR2/CD21–) B cells have been found enriched in patients with autoimmune diseases and in common variable immunodeficiency (CVID) patients who are prone to autoimmunity. However, the physiology of CD21–/lo B cells remains poorly characterized. We found that some rheumatoid arthritis (RA) patients also display an increased frequency of CD21–/lo B cells in their blood. A majority of CD21–/lo B cells from RA and CVID patients expressed germline autoreactive antibodies, which recognized nuclear and cytoplasmic structures. In addition, these B cells were unable to induce calcium flux, become activated, or proliferate in response to B-cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. Moreover, gene array analyses of CD21–/lo B cells revealed molecules specifically expressed in these B cells and that are likely to induce their unresponsive stage. Thus, CD21–/lo B cells contain mostly autoreactive unresponsive clones, which express a specific set of molecules that may represent new biomarkers to identify anergic B cells in humans.
2009-12-01 | GSE13917 | GEO
Project description:We investigated how Tfh cells contribute to the breakdown of peripheral immune tolerance and the formation of autoimmune lesions in a murine model of SS. Our results indicate a yet unreported mechanism of autoreactive response through Tfh cells in a SS model mouse, and it will be supportive for understanding the pathogenesis of autoimmunity.
2018-12-05 | GSE123332 | GEO
Project description:Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene segregates with most autoimmune diseases; its risk allele encodes overactive PTPN22 phosphatases that alter B cell receptor (BCR) signaling potentially involved in the regulation of central B cell tolerance. To assess whether PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s). We found that new emigrant/transitional and mature naive B cells from PTPN22 risk allele carriers contained high frequencies of autoreactive clones compared to non-carrier control donors. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection, suggesting that early B cell tolerance checkpoint defects precede the onset of autoimmunity. In addition, gene array experiments comparing mature naïve B cells from healthy individuals carrying or not PTPN22 risk allele(s) revealed that the strength of association of PTPN22 for autoimmunity, second in importance only to the MHC, may not only be due to BCR signaling alteration but also to the regulation of other genes, which themselves have also been identified as involved in the development of autoimmune diseases. The PTPN22 risk allele is a single nucleotide change (cytidine to thymidine) at residue 1858, which results in a single amino acid substitution from arginine to tryptophan at position 620 of the PTPN22/Lyp protein. Data from mature naïve B cell populations from patients carrying 1 or 2 PTPN22 T alleles and non-carrier patients were compared in order to characterize the impact of PTPN22 polymorphism on B cell physiology. RNA was extracted from batch-sorted CD19+CD10-CD21+CD27- conventional mature naive B cells using the Absolutely RNA microprep kit (Stratagene). 100-200 ng of RNA was obtained per sample, and the quality of the purified RNA was assessed by the Bioanalyzer from Agilent. Using the Ovation biotin system kit from Nugen, 30-50ng of RNA was amplified and labeled to produce cDNA. Labeled cDNA was hybridized on chips containing the whole human genome (Human Genome U133 Plus 2.0 from Affymetrix).
2010-10-16 | E-GEOD-24736 | biostudies-arrayexpress