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BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8⁺ T cells.

ABSTRACT: During chronic infection and cancer, a self-renewing CD8⁺ T cell subset maintains long-term immunity and is critical to the effectiveness of immunotherapy. These stem-like CD8⁺ T cells diverge from other CD8⁺ subsets early after chronic viral infection. However, pathways guarding stem-like CD8⁺ T cells against terminal exhaustion remain unclear. Here, we show that the gene encoding transcriptional repressor BACH2 is transcriptionally and epigenetically active in stem-like CD8⁺ T cells but not terminally exhausted cells early after infection. BACH2 overexpression enforced stem-like cell fate, whereas BACH2 deficiency impaired stem-like CD8⁺ T cell differentiation. Single-cell transcriptomic and epigenomic approaches revealed that BACH2 established the transcriptional and epigenetic programs of stem-like CD8⁺ T cells. In addition, BACH2 suppressed the molecular program driving terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a new pathway that enforces commitment to stem-like CD8⁺ lineage and prevents an alternative terminally exhausted cell fate.

SUBMITTER: Yao C

PROVIDER: S-EPMC7906956 | biostudies-literature |

REPOSITORIES: biostudies-literature

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BACH2 Establishes the Transcriptional and Epigenetic Programs of Stem-Like CD8 T cells

Project description:During chronic infection and cancer, a self-renewing CD8 T cell subset maintains long-term T-cell immunity and mediate the response induced by immunotherapy. These stem-like CD8 T cells diverge from other CD8 subsets early in the immune response and display distinct transcriptional and epigenetic signatures. Here, we show that locus encoding transcriptional factor BACH2 is transcriptionally and epigenetically active in stem-like CD8 T cells but not in terminally exhausted CD8 T cells. Overexpression of BACH2 enforces the stem-like cell fate, whereas Bach2 deficiency impairs stem-like CD8 T cell differentiation. Using single-cell transcriptomics and epigenomics approaches, we demonstrate BACH2 as a key regulator of the transcriptional and epigenetic programs of stem-like CD8 T cells. In addition, BACH2 suppresses genes and pathways that drive terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a novel pathway responsible for establishing the unique transcriptional and epigenetic program of stem-like CD8 T cells.

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SATB1 ensures appropriate transcriptional programs within naive CD8+ T cells.

Project description:Special AT-binding protein 1 (SATB1) is a chromatin-binding protein that has been shown to be a key regulator of T-cell development and CD4+ T-cell fate decisions and function. The underlying function for SATB1 in peripheral CD8+ T-cell differentiation processes is largely unknown. To address this, we examined SATB1-binding patterns in naïve and effector CD8+ T cells demonstrating that SATB1 binds to noncoding regulatory elements linked to T-cell lineage-specific gene programs, particularly in naïve CD8+ T cells. We then assessed SATB1 function using N-ethyl-N-nitrosourea-mutant mice that exhibit a point mutation in the SATB1 DNA-binding domain (termed Satb1m1Anu/m1Anu ). Satb1m1Anu/m1Anu mice exhibit diminished SATB1-binding, naïve, Satb1m1Anu/m1Anu CD8+ T cells exhibiting transcriptional and phenotypic characteristics reminiscent of effector T cells. Upon activation, the transcriptional signatures of Satb1m1Anu/m1Anu and wild-type effector CD8+ T cells converged. While there were no overt differences, primary respiratory infection of Satb1m1Anu/m1Anu mice with influenza A virus (IAV) resulted in a decreased proportion and number of IAV-specific CD8+ effector T cells recruited to the infected lung when compared with wild-type mice. Together, these data suggest that SATB1 has a major role in an appropriate transcriptional state within naïve CD8+ T cells and ensures appropriate CD8+ T-cell effector gene expression upon activation.

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BACH2 Establishes the Transcriptional and Epigenetic Programs of Stem-Like CD8 T cells

Project description:BACH2 Establishes the Transcriptional and Epigenetic Programs of Stem-Like CD8 T cells

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PRMT5 deficiency enforces the transcriptional and epigenetic programs of Klrg1+CD8+ terminal effector T cells

Project description:This SuperSeries is composed of the SubSeries listed below.

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