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Loss of RPA1 impairs peripheral T cell homeostasis and exacerbates inflammatory damage through triggering T cell necroptosis

ABSTRACT: The peripheral T cell pool is maintained at dynamic homeostasis throughout life. This is achieved through fine-tuning of thymic output and self-renewal of naïve T cells. Dysregulation of T cell homeostasis has been implicated in autoimmune diseases, yet little is known about the homeostatic mechanisms. Here, we report that the replication protein A1 (RPA1) is upregulated during T cell activation. Utilizing T cell-specific Rpa1-deficient (Rpa1fl/fl Cd4-cre) mice, we find that loss of Rpa1 restrains peripheral CD8+ T cell population and limits TCR repertoire diversity. Clinical analysis reveals that the mRNA level of RPA1 is reduced in patients with ulcerative colitis. Accordingly, Rpa1fl/fl Cd4-cre mice exhibit increased susceptibility to inflammatory diseases, including colitis and hepatitis. Mechanistically, RPA1 deficiency triggers necroptotic T cell death following TCR engagement, which in turn results in damage-associated molecular patterns (DAMPs) leakage and leukocyte recruitment, consequently exacerbating inflammatory damage. These studies thus uncover that RPA1 acts as a guardian of T cell clonal expansion that is essential for T cell homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE217030 | GEO | 2024/11/30

REPOSITORIES: GEO

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Project description:Transforming growth factor-Î² (TGF-Î²) has been implicated in the control of differentiation and proliferation of multiple cell types. However, a role for TGF-Î² in the control of immune homeostasis is not fully understood because of its pleiotropic action. Here we report that complete ablation of the TGF-Î² signaling in T cells engendered aggressive early-onset, multiorgan, autoimmune-associated lesions with 100% mortality. Peripheral CD4+ and CD8+ T cells with TGF-Î²-receptor II (TGF-Î²RII) deficiency activated cytolytic and T helper 1 (Th1) differentiation program in a cell-intrinsic T cell receptor (TCR)-specific fashion. Furthermore, TGF-Î²RII deficiency blocked the development of canonical CD1d-restricted NKT cells. Instead, it facilitated generation of a highly pathogenic T cell subset exhibiting multiple hallmarks of NK cells and sharply elevated amounts of FasL, perforin, granzymes, and interferon-Î³. Thus, TGF-Î² signaling in peripheral T cells is crucial in restraining TCR activation-dependent Th1, cytotoxic, and NK cell-like differentiation program which, when left unchecked, leads to rapidly progressing fatal autoimmunity. Experiment Overall Design: To better understand the basis for pathogenicity of TGF-Î²RII-deficient NK1.1+ T cells, we performed gene expression profiling of NK1.1+ and NK1.1â T cell subsets from Tgfbr2fl/fl x CD4-Cre mice. We limited our analysis to CD8+ T cell subsets because NK1.1+ CD8 T cells made up 70% of total NK1.1+ T cells in Tgfbr2fl/fl x CD4-Cre mice, and this T cell subset showed the greatest numerical increase compared to littermate control mice. Thus, in these experiments we used FACS-sorted NK1.1+ and NK1.1â CD8+ T cells from 15- to 17-day-old mutant mice and total CD8+ T cells from Tgfbr2fl/wt x CD4-Cre littermate controls. Experiment Overall Design: mRNA expression profiles of NK1.1+ and NK1.1â CD8+ T cells from Tgfbr2fl/fl x CD4-Cre (KO) mice were compared to NK1.1â T cells from littermate control Tgfbr2fl/WT x CD4-Cre (Control) mice.

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Loss of RPA1 impairs peripheral T cell homeostasis and exacerbates inflammatory damage through triggering T cell necroptosis

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