Non-deletional CD8+ T cell self-tolerance permits responsiveness but limits tissue damage
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA718819 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14118845_1.fastq.gz | Fastqsanger.gz | |||
| SRR14118845_2.fastq.gz | Fastqsanger.gz | |||
| SRR14118846_1.fastq.gz | Fastqsanger.gz | |||
| SRR14118846_2.fastq.gz | Fastqsanger.gz | |||
| SRR14118847_1.fastq.gz | Fastqsanger.gz |
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Project description:Self-specific CD8+ T cells often escape clonal deletion, but the properties and capabilities of such cells in a physiological setting are unclear. We characterized polyclonal CD8+ T cells specific for the melanocyte antigen tyrosinase-related protein 2 (Trp2) in mice that express or lack this enzyme due to deficiency in Dct, which encodes Trp2. The size, phenotype, and gene expression profile of the pre-immune Trp2/Kb-specific pool were similar in wild-type (WT) and Dct-deficient (Dct-/-) mice. Despite comparable initial responses to Trp2 immunization, WT Trp2/Kb-specific cells showed blunted expansion, and scRNAseq revealed WT cells less readily differentiated into a CD25+ proliferative population. Functional self-tolerance clearly emerged when assessing immunopathology: adoptively transferred WT Trp2/Kb-specific cells mediated vitiligo much less efficiently. Hence, CD8+ T cell self-specificity is poorly predicted by precursor frequency, phenotype or even initial responsiveness, while deficient activation-induced CD25 expression and other gene expression characteristics may help to identify functionally tolerant cells.
2021-04-30 | GSE171221 | GEO
Project description:Self-specific CD8+T cells can escape clonal deletion, but the properties and capabilities of such cells in a physiological setting are unclear. We characterized polyclonal CD8+ T cells specific for the melanocyte antigen tyrosinase-related protein 2 (Trp2) in mice expressing or lacking this enzyme (due to deficiency in Dct, which encodes Trp2). Phenotypic and gene expression profiles of pre-immune Trp2/Kb-specific cells were similar; the size of this population was only slightly reduced in wild-type (WT) compared to Dct-deficient (Dct-/-) mice. Despite comparable initial responses to Trp2 immunization, WT Trp2/Kb-specific cells showed blunted expansion and less readily differentiated into a CD25+proliferative population. Functional self-tolerance clearly emerged when assessing immunopathology: adoptively transferred WT Trp2/Kb-specific cells mediated vitiligo much less efficiently. Hence, CD8+ T cell self-specificity is poorly predicted by precursor frequency, phenotype, or even initial responsiveness, while deficient activation-induced CD25 expression and other gene expression characteristics may help to identify functionally tolerant cells.
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Project description:MTD project_description Inflammation and decreased stem cell function characterize organism aging, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signals, by increasing chromatin accessibility of inter-/intra-genic and enhancer regions. Rad21/NF-κB are required for normal differentiation, but limit self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB dependent manner. HSCs from aged mice fail to downregulate Rad21/cohesin and inflammation/differentiation inducing signals in the resolution phase after acute inflammation. and The inhibition of cohesin/NF-κB is sufficient to revert the hypersensitivity of aged HSPCs to inflammation-induced differentiation. During aging, myeloid-biased HSCs with disrupted and naturally occurring reduced expression of Rad21/cohesin are increasingly selected over lymphoid-biased HSCs. Together, Rad21/cohesin mediated NF-κB signaling limits HSPC function during aging and selects for cohesin deficient HSCs with myeloid skewed differentiation.
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Project description:Self-tolerance maintained by self-reactive CD8+ T cells
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Project description:The diverse T cell receptor (TCR) repertoire – generated randomly through VDJ recombination early in development – is inherently self-reactive. Clonal deletion and diversion to regulatory T cell (Treg) fate are key central tolerance mechanisms engaged during thymic selection. The NR4A family of transcription factors has been implicated in both, but the extent of its contribution to clonal deletion and the transcriptional mechanisms at play remain unknown. Here, we investigated both NR4A-dependent and NR4A-independent transcriptional changes induced in developing thymocytes in response to model self-antigen presented by medullary thymic epithelial cells (mTECs). To do so, we took advantage of the MHCII-restricted TCR transgene OTII and model self-antigen (membrane-bound ovalbumin expressed under the control of the rat insulin promoter encoded by the RIP-mOVA transgene). Our results suggest that a surprisingly broad transcriptional program is enacted upon high affinity self-antigen encounter in the thymus. Furthermore, by investigating the expression profile of OTII Nr4a1-/- Nr4a3-/- double knock-out (OTII-DKO) thymocytes that receive high affinity antigen-dependent signal but escape both clonal deletion and Treg diversion, we reveal evidence for deletional and non-deletional central tolerance mechanisms.
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Project description:CD8+ T cells play a critical role in immune tolerance maintainnance after immune activation. It is known to function through targeting activated CD4+ T cells, in both Qa-1- and MHC-Ia-restricted9 manner. However, the exact nature of this targeting process, i.e., the specific peptides and the corresponding reactive CD8 TCRs, remains unknown. In this study, we identified the self-peptides on activated CD4+ T cells that could mediate the CD8+ T cells immunosuppressive activity. By cloning the corresponding CD8 TCRs and the generation of TCR transgenic mice , we were able to validate the immunosuppressive function of CD8+ T cells carrying the self-reactive TCRs both in vitro and in vivo. The therapeutic potential of peptide vaccination and CD8+ T cell transfer were confirmed in a mouse EAE model. This study suggest that self-tolerance can be maintained by self-reactive CD8+ T cells recognizing self-antigenic peptides through specific TCRs, thus redefine the nature of CD8+ regulatory T cells as self-reactive CD8+ T cells.
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Project description:Preventing autoantibody secretion by rendering self-reactive B cells functionally silent through clonal anergy has long posed the question of why fill the circulating B cell repertoire with cells that cannot secrete antibody? Here we address this question from the perspective of B cells that comprise 5-10% of the human circulating repertoire, expressing self-reactive surface immunoglobulins employing the IGHV4-34 heavy chain variable element. Using gene targeting to construct mice expressing a representative human IGHV4-34 antibody on the surface of many B cells, we show these cells are prevented from autoantibody secretion by B cell clonal anergy marked by downregulation of surface IgM, induction of tolerance-response mRNAs, and exclusion from the marginal zone and B1 cell subsets. This functionally tolerant state is overridden when the IGHV4-34 B cells cross-react with a virus, which stimulates the self-reactive B cells to hypermutate in germinal centres. Within 16 days of infection, 99% of daughter cells have acquired one of five heavy chain mutations that diminish binding to self but preserve virus binding, and 33% had combined 2 or 3 of these mutations to become genetically self-tolerant and virus specific. These results demonstrate, from the perspective of a pathologically important human autoantibody class and the world’s most successful virus vaccine, how human antibody specificity is sculpted in the progeny of anergic B cells to yield antibodies that bind a virus but not self.
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