Abstract
STAT1 is an essential part of interferon signaling, and STAT1-deficiency results in heightened susceptibility to infections or autoimmunity in both mice and humans. Here we report that mice lacking the IFNα/β-receptor (IFNAR1) or STAT1 display impaired deletion of autoreactive CD4+CD8+-T-cells. Strikingly, co-existence of WT T cells restored thymic elimination of self-reactive STAT1-deficient CD4+CD8+-T cells. Analysis of STAT1-deficient thymocytes further revealed reduced Bim expression, which was restored in the presence of WT T cells. These results indicate that type I interferons and STAT1 play an important role in the survival of MHC class I-restricted T cells in a T cell intrinsic and non-cell intrinsic manner that involves regulation of Bim expression through feedback provided by mature STAT1-competent T cells.
Highlights
Selection of T lymphocytes expressing antigen receptors that are major histocompatibility complex (MHC)-restricted but tolerant to self-antigens is a fundamental prerequisite for a functional immune system
In order to investigate a possible function for signal transducer and activator of transcription 1 (STAT1) in thymic selection events, STAT1-deficient mice were crossed with TCRHY transgenic animals yielding TCRHYSTAT12/2 animals
The absence of STAT1 resulted in a drastic impairment of this elimination process such that a substantial number of CD4+CD8+-double positive and CD8+-single positive thymocytes were detectable in male TCRHYSTAT12/2 mice (Fig. 1a, 2nd panel)
Summary
Selection of T lymphocytes expressing antigen receptors that are major histocompatibility complex (MHC)-restricted but tolerant to self-antigens is a fundamental prerequisite for a functional immune system. CD4+CD8+-thymocytes mature into CD4+ or CD8+ single positive T cells via a dual selection process. If the TCRs of positively selected T cells subsequently engage in high affinity interactions with the MHC/peptide complex on stromal cells such as dendritic cells and macrophages, these T cells are deleted from the pool via programmed cell death. Thereby, the process of negative selection eliminates self-reactive thymocytes and facilitates tolerance to selfantigens. The outcomes of these two selection processes are required to generate a T cell repertoire that is both self-MHC restricted and self-tolerant, a process that appears to be determined by the avidity between the MHC/peptide complex and the TCR [1,2,3,4]
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