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 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.

Immunology & Cell Biology's Top 10 original research articles 2021–2022

“…Peripheral B‐cell dysregulation is associated with relapse after long‐term quiescence in patients with multiple sclerosis. English et al 9 . The liver contains distinct interconnected networks of CX3CR1 + macrophages, XCR1 + type 1 and CD301a + type 2 conventional dendritic cells embedded within portal tracts. Nüssing et al 10 . SATB1 ensures appropriate transcriptional programs within naïve CD8 + T cells.…”

“…6,10 Comparing the null allele found in C57BL/6 mice with a corrected and functional CXCL11, Dalit et al 6 comprehensively showed that the B-and T-cell responses and germinal center formation were unaffected by the loss of CXCL11 function during influenza or LCMV infections despite the known importance of its receptor, CXCR3, in Th1 and CD8 + T-cell responses. In contrast, N€ ussing et al 10 demonstrated the importance of SATB1, which is known to be involved in T-cell development and CD4 + T-cell fate decisions, in the generation of influenza A-specific CD8 + T cells. Using bone-marrow chimeric mice with a point mutation in SATB1 leading to diminished binding, they further identified that the defect in virus-specific CD8 + T cells was cell-specific.…”

“…• N€ ussing et al 10 SATB1 ensures appropriate transcriptional programs within na€ ıve CD8 + T cells.…”

“…3 Dalit et al and N€ ussing et al also assess the role of specific immune components during influenza infection, but instead of antibody, they focus on the IFN-inducible chemokine, CXCL11, and the chromatin-binding protein, SATB1. 6,10 Comparing the null allele found in C57BL/6 mice with a corrected and functional CXCL11, Dalit et al 6 comprehensively showed that the B-and T-cell responses and germinal center formation were unaffected by the loss of CXCL11 function during influenza or LCMV infections despite the known importance of its receptor, CXCR3, in Th1 and CD8 + T-cell responses. In contrast, N€ ussing et al 10 demonstrated the importance of SATB1, which is known to be involved in T-cell development and CD4 + T-cell fate decisions, in the generation of influenza A-specific CD8 + T cells.…”

“…Using bone-marrow chimeric mice with a point mutation in SATB1 leading to diminished binding, they further identified that the defect in virus-specific CD8 + T cells was cell-specific. 10 These articles highlight the complex network of immune factors involved in protection from influenza with each factor contributing unique and sometimes subtle activities. and Langerhans cells) in the lymph nodes, and when genetically deleted from mice, the absence of this RNAbinding protein led to lymphadenopathy.…”