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STAT1 maintains naive CD8⁺ T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis.

ABSTRACT: Naïve CD8⁺ T cell quiescence is maintained at a steady state. Although this state of quiescence involves various cell-intrinsic and cell-extrinsic regulators, the mechanisms underlying this regulation remain incompletely understood. Here, we found that signal transducer and activator of transcription 1 (STAT1), a key transcription factor downstream of interferon receptor (IFNR) signaling, plays a cell-intrinsic role in maintaining naïve CD8⁺ T cell quiescence. STAT1-deficient mice showed enhanced proliferation of peripheral naïve CD8⁺ T cells, which resulted in an abnormal increase in the number of CD44^hi memory/activated phenotype cells and an enlargement of secondary lymphoid tissues. This phenomenon was not observed in IFNR-deficient mice but was paradoxically dependent on type I interferon and its alternative signaling pathway via the STAT4–RagD–lysosomal mTORC1 axis. Collectively, these findings underline the importance of STAT1 in regulating the homeostasis of peripheral naïve CD8⁺ T cells by suppressing their responsiveness to homeostatic cues at a steady state.

SUBMITTER: Kye YC

PROVIDER: S-EPMC8442933 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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STAT1 maintains naïve CD8+ T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis.

Kye Yoon-Chul YC Lee Gil-Woo GW Lee Sung-Woo SW Ju Young-Jun YJ Kim Hee-Ok HO Yun Cheol-Heui CH Cho Jae-Ho JH

Science advances 20210901 36

Naïve CD8+ T cell quiescence is maintained at a steady state. Although this state of quiescence involves various cell-intrinsic and cell-extrinsic regulators, the mechanisms underlying this regulation remain incompletely understood. Here, we found that signal transducer and activator of transcription 1 (STAT1), a key transcription factor downstream of interferon receptor (IFNR) signaling, plays a cell-intrinsic role in maintaining naïve CD8+ T cell quiescence. STAT1-deficie ...[more]

PMID: 34516905

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Project description:BackgroundSpinal cord injury (SCI) causes nearly all patients to suffer from protracted disabilities. An emerging therapeutic strategy involving the recruitment of endogenous neural stem cells (NSCs) has been developed. However, endogenous NSCs in the adult spinal cord differentiate into mostly astrocytes after traumatic injury, forming glial scars, which is a major cause of regeneration failure in SCI. Thus, understanding which factors drive the activation and differentiation of endogenous NSCs after SCI is critical for developing therapeutic drugs.MethodsThe infiltration, state, and location of CD8+ T cells in spinal cord after traumatic injury were analyzed by flow cytometry and immunofluorescence (IF) staining. The Basso Mouse Scale (BMS) scores and rotarod testing were used for motor behavioral analysis. NSCs were co-cultured with CD8+ T cells. EdU assay was used to detect proliferative cells. Western blotting was used to analyze the expression levels of STAT1, p-STAT1, and p27. ChIP-seq and ChIP-qRT-PCR analyses were used to detect the downstream of STAT1. Nestin-CreERT2::Ai9 transgenic mice were used to genetic lineage tracing of Nestin+ NSCs after SCI in vivo.ResultsA prolonged increase of activated CD8+ T cells occurs in the injured spinal cords. The behavioral analysis demonstrated that the administration of an anti-CD8 antibody promotes the recovery of locomotor function. Then, we discovered that CD8+ T cells suppressed the proliferation of NSCs and promoted the differentiation of NSCs into astrocytes by the IFN-γ-STAT1 pathway in vitro. ChIP-seq and ChIP-qRT-PCR analysis revealed that STAT1 could directly bind to the promoters of astrocyte marker genes GFAP and Aldh1l1. Genetic lineage tracing of Nestin+ NSCs demonstrated that most NSCs differentiated into astrocytes following SCI. Depleting CD8+ T cells reduced the differentiation of NSCs into astrocytes and instead promoted the differentiation of NSCs into oligodendrocytes.ConclusionIn conclusion, CD8+ T cells suppressed the proliferation of NSCs and promoted the differentiation of NSCs into astrocytes by the IFN-γ-STAT1-GFAP/Aldhl1l axis. Our study identifies INF-γ as a critical mediator of CD8+ T-cell-NSC cross talk and a potential node for therapeutic intervention in SCI.

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STAT1 maintains naive CD8⁺ T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis.

Publications

STAT1 maintains naïve CD8<sup>+</sup> T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis.

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Dataset Information

STAT1 maintains naive CD8+ T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis.

Publications

STAT1 maintains naïve CD8<sup>+</sup> T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

STAT1 maintains naive CD8⁺ T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis.