SATB1 ensures appropriate transcriptional programs within naïve CD8+ T cells

Abstract

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 Satb1^m1Anu/m1Anu ). Satb1^m1Anu/m1Anu mice exhibit diminished SATB1-binding, naïve, Satb1^m1Anu/m1Anu CD8⁺ T cells exhibiting transcriptional and phenotypic characteristics reminiscent of effector T cells. Upon activation, the transcriptional signatures of Satb1^m1Anu/m1Anu and wild-type effector CD8⁺ T cells converged. While there were no overt differences, primary respiratory infection of Satb1^m1Anu/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.

Keywords: CD8+ T cell; chromatin; influenza A virus; memory T cell; naïve T cell.