Abstract
Special AT‐rich binding protein‐1 (SATB1) is a global chromatin organizer capable of activating or repressing gene transcription in mice and humans. The role of SATB1 is pivotal for T‐cell development, with SATB1‐knockout mice being neonatally lethal, although the exact mechanism is unknown. Moreover, SATB1 is dysregulated in T‐cell lymphoma and proposed to suppress transcription of the Pdcd1 gene, encoding the immune checkpoint programmed cell death protein 1 (PD‐1). Thus, SATB1 expression in T‐cell subsets across different tissue compartments in humans is of potential importance for targeting PD‐1. Here, we comprehensively analyzed SATB1 expression across different human tissues and immune compartments by flow cytometry and correlated this with PD‐1 expression. We investigated SATB1 protein levels in pediatric and adult donors and assessed expression dynamics of this chromatin organizer across different immune cell subsets in human organs, as well as in antigen‐specific T cells directed against acute and chronic viral infections. Our data demonstrate that SATB1 expression in humans is the highest in T‐cell progenitors in the thymus, and then becomes downregulated in mature T cells in the periphery. Importantly, SATB1 expression in peripheral mature T cells is not static and follows fine‐tuned expression dynamics, which appear to be tissue‐ and antigen‐dependent. Furthermore, SATB1 expression negatively correlates with PD‐1 expression in virus‐specific CD8+ T cells. Our study has implications for understanding the role of SATB1 in human health and disease and suggests an approach for modulating PD‐1 in T cells, highly relevant to human malignancies or chronic viral infections.
Highlights
Special AT-rich sequence-binding protein 1 (SATB1) is a chromatin organizer and transcription factor[1,2] that gained increasing interest over recent years as a tumor marker
Previous studies in Special AT-rich binding protein-1 (SATB1)-null mice demonstrated an essential role of SATB1 in T-cell development in murine thymi, with thymocyte development being mainly blocked at the CD4+CD8+ double positive stage, leading to a very limited number of single-positive CD4+ and CD8+ T cells migrating to the periphery.[2]
We extended these findings to humans and investigated the kinetics of SATB1 expression across different human tissue compartments and ages
Summary
Special AT-rich sequence-binding protein 1 (SATB1) is a chromatin organizer and transcription factor[1,2] that gained increasing interest over recent years as a tumor marker. SATB1 originally was described to be expressed in Tcell populations, especially in the thymus.[1,2,10] Essential roles of SATB1 in organizing temporal and spatial expression of genes were shown for T-cell development in murine thymi after the generation of SATB1-null mice.[2]. SATB1-null mice had small thymi and spleens and were fatal by the age of 3 weeks. Thymocyte development was blocked at the CD4+CD8+ double-positive (DP) stage as only a few CD4+ and CD8+ single-positive T cells survive and migrate to the periphery in SATB1-null mice.[2]
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