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Nonspecific induction of distinct regulatory T cell states in oncogene-driven hyperproliferative skin

ABSTRACT: Regulatory T cells (Tregs) recruited to peripheral tissues are associated with chronic diseases such as cancer. Tissue-specific signals and T cell receptor (TCR) specificity are critical to shape Treg phenotype diversity. We examined single-cell transcriptomic and TCR profiles of Tregs in human papillomavirus (HPV) E7-transformed hyperproliferative skin of mice. Tregs without evidence of E7 specificity were enriched in E7 transgenic skin grafts when compared with non-transgenic grafts. E7 transgenic skin grafts contained more Klrg1+ Tregs and Il1r2+ Tregs than non-transgenic grafts. These two Treg states had distinct effector phenotypes but shared a core gene signature with previously described tumour-infiltrating Tregs. Pseudotime trajectory of Tregs predicted phenotypic plasticity of TCR clonotypes, both within skin and between skin and draining lymph nodes. Together, we reveal that oncogene-driven hyperproliferative skin enables induction of nonspecific Tregs despite the presence of non-self antigen and Tregs exist in distinct cell states with unique effector gene signatures.

ORGANISM(S): Mus musculus

PROVIDER: GSE156745 | GEO | 2021/01/28

REPOSITORIES: GEO

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Project description:The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions1. Activation of mTOR, comprised of mTORC1 and mTORC2 complexes, delivers an obligatory signal for proper activation and differentiation of effector CD4+ T cells2,3, whereas in the regulatory T cell (Treg) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of Treg de novo differentiation4-8 and population expansion9. However, whether mTOR signaling affects the homeostasis and function of Tregs remains largely unexplored. Here we show that mTORC1 signaling is a pivotal positive determinant of Treg function. Tregs have elevated steady-state mTORC1 activity compared to naïve T cells. Signals via T cell receptor (TCR) and IL-2 provide major inputs for mTORC1 activation, which in turn programs suppressive function of Tregs. Disruption of mTORC1 through Treg-specific deletion of the essential component Raptor leads to a profound loss of Treg suppressive activity in vivo and development of a fatal early-onset inflammatory disorder. Mechanistically, Raptor/mTORC1 signaling in Tregs promotes cholesterol/lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg proliferation and upregulation of suppressive molecules CTLA-4 and ICOS to establish Treg functional competency. In contrast, mTORC1 does not directly impact the expression of Foxp3 or anti- and pro-inflammatory cytokines in Tregs, suggesting a non-conventional mechanism for Treg functional regulation. Lastly, we provide evidence that mTORC1 maintains Treg function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Tregs to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg suppressive activity in immune homeostasis and tolerance. We used microarrays to explore the gene expression profiles differentially expressed in regulatory T-cells from wild-type and CD4(cre) x Raptor(fl/fl) mice

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Nonspecific induction of distinct regulatory T cell states in oncogene-driven hyperproliferative skin

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