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Transcriptional control of central T cell tolerance by NR4A family transcription factors

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE235101 | GEO | 2024/05/20

REPOSITORIES: GEO

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Project description:Peripheral tolerance induction is critical for the maintenance of self-tolerance and can be mediated by immunoregulatory T cells or by direct induction of T cell anergy or deletion. While the molecular processes underlying anergy have been extensively studied, little is known about the molecular basis for peripheral T cell deletion. Here, we determined the gene expression signature of peripheral CD8+ T cells undergoing deletional tolerance, relative to those undergoing immunogenic priming or lymphopenia-induced proliferation. From these data, we report the first detailed molecular signature of cells undergoing deletion. Consistent with defective cytolysis, these cells exhibited deficiencies in granzyme up-regulation. Furthermore, they showed antigen-driven Bcl-2 down-regulation and early up-regulation of the pro-apoptotic protein Bim, consistent with the requirement of this BH3-only protein for peripheral T cell deletion. Bim up-regulation was paralleled by defective IL-7Ra chain re-expression, suggesting that Bim-dependent death may be triggered by loss of IL-7/IL-7R signaling. Finally, we observed parallels in molecular signatures between deletion and anergy suggesting that these tolerance pathways may not be as molecularly distinct as previously surmised. NaÃ¯ve (CD44lo) OT-I T cells were CFSE labelled and transferred in a model of deletional tolerance (RIP-OVAhi mice), a model of immunity (mice primed with OVA coated splenocytes and LPS) or a model of lymphopenia induced proliferation (Rag-/- mice). 60 hrs (RIP-OVAhi and OVA coated splenocytes) or 5 days (Rag-/-) after transfer, OT-I cells that had undergone two or more divisions as determined by CFSE dilution were sorted, RNA extracted and samples were prepared for hybridisation to Affymetrix microarrays. As a control for naive cells, CFSE labelled OT-I cells were injected into antigen-free B6 mice and the undivided naive cells were sorted after 60 hrs and also used for microarray analysis. Two replicates were prepared for the naive cells, cells from RIP-OVAhi mice and cells from OVA coated splenocyte primed mice, while one replicate was prepared for the cells from Rag-/- mice.

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Transcriptional control of central T cell tolerance by NR4A family transcription factors

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