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The frequency of antigen-specific T cells is regulated by self-specific non-clonal neighbors

ABSTRACT: In order to repeatedly mount successful immune responses against a wide range of pathogens, vertebrates must maintain sufficient numbers of diversely specific T cells over a long time. The cellular principles ensuring this are not clear. We show that the density of an antigen-specific T cell population is regulated by neighboring T cells not specific for the same antigen. Their activity is nevertheless T cell specific, due to the shared recognition of a self-peptide. Such regulation was sufficient to prevent autoimmune arthritis even in a lymphopenic model system without other regulatory T cells. This homeostatic strategy, based on the specific recognition of unique sub-threshold ligands, avoids excessive loss of bystander specificities during multiple immune responses, preserving the valuable diversity of the T cell repertoire.

ORGANISM(S): Mus musculus

PROVIDER: GSE35220 | GEO | 2013/01/01

SECONDARY ACCESSION(S): PRJNA150651

REPOSITORIES: GEO

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Project description:Tumors express a wide variety of both mutated and non-mutated antigens. Whether these tumor antigens are broadly recognized as âselfâ or âforeignâ by the immune system is currently unclear. Using an autochthonous prostate cancer model in which hemagglutinin (HA) is specifically expressed in the tumor (ProHA x TRAMP mice), as well as an analogous model wherein HA is expressed in normal tissues as a model self-antigen (C3HAHigh), we examined the transcriptional profile of CD4 T cells undergoing antigen-specific division. Consistent with our previous data, transfer of antigen-specific CD4 T cells into C3HAHigh resulted in a functionally inactivated CD4 T cell profile. Conversely, adoptive transfer of an identical CD4 T cell population into ProHA x TRAMP resulted in the induction of a regulatory phenotype (Treg) both at the transcriptional and functional level. Interestingly, this Treg skewing was a property of even early-stage tumors, suggesting Treg induction as an important tolerance mechanism during tumor development. The goal of this microarray is to detail the transcriptional profile differences between CD4 T cells that recognize their cognate antigen in the context of tumor (ProHA x TRAMP model) or self-antigen recognition (C3HA) or viral-antigen recognition (VaccHA) models or unprimed naÃ¯ve state (Nontransgenic). The comparison contains both upregulated and downregulated transcripts. Experiment Overall Design: TCR transgenic CD4 T cells specific for hemagglutinin (HA) were adoptively transferred into tumor-antigen recognition model (ProHA x TRAMP), Self-antigen recognition model (C3HA), viral-antigen recognition model (VaccHA), and naÃ¯ve control (Nontrangenic). Divided (CFSE diluted) CD4 T cells were sorted by FACS, RNA was extracted, and biological replicated were hybridized to an Affymetrix Mouse 430 Plus 2 expression array, followed by interrogation with an Affymetrix GeneChip Scanner 3000. RMA normalization was employed to identify differentially expressed transcripts.

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The frequency of antigen-specific T cells is regulated by self-specific non-clonal neighbors

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