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Tolerogenic transcriptome landscape in CD8+ T lymphocytes after exposure to erythrocyte-targeted antigen

ABSTRACT: Our group has recently shown induction of antigen-specific T cell tolerance through targeting antigen to erythrocytes in situ, based on the premise that as the erythrocytes age and are cleared eryptotically, their carried antigen payload is processed tolerogenically. The tolerogenic state is characterized by initial proliferation of antigen-specific CD4+ and CD8+ T cells, and subsequent acquisition of deletional, anergic and CD25+FOXP3+ regulatory T cell phenotypes. In this study, we wished to further understand the molecular mechanisms behind induction of tolerance by erythrocyte-targeted antigens. RNA sequencing was performed to determine how genes are regulated in tolerized ovalbumin-specific CD8+ T cells and which pathways are activated after treatment with this technology. High similarity between the gene response reported during self-tolerance, deletional tolerance and tolerance induced by erythrocyte-targeted antigens was observed. Treatment with erythrocyte-targeted antigens led to the upregulation of genes encoding several TCR co-inhibitory receptors such as CTLA4, PD1, LAG3, TIGIT and CD200R1, and lack of upregulation of cytotoxic and pro-inflammatory signaling molecule genes. Modulation in expression of the master transcription factors Egr2/NFatc1, Nur77 family and E2f1 was also observed, all known to be associated with the process of peripheral tolerance. Expression of these genes differed in response to treatment with soluble ovalbumin or free SIINFEKL MHCI peptide, suggesting a specific mechanism of T cell modulation and tolerance induction in response to the erythrocyte-associated forms. Together these results provide novel insights to further understand the mechanisms and potential of erythrocyte-targeted antigens for induction of antigen-specific immune tolerance.

ORGANISM(S): Mus musculus

PROVIDER: GSE98590 | GEO | 2020/05/05

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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Tolerogenic transcriptome landscape in CD8+ T lymphocytes after exposure to erythrocyte-targeted antigen

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