Stiftung Tierärztliche Hochschule Hannover (TiHo)

Divergent SATB1 expression across human life span and tissue compartments

Nüssing, Simone; Koay, Hui-Fern ORCID; Sant, Sneha; Loudovaris, Thomas; Mannering, Stuart I.; Lappas, Martha ORCID; d'Udekem, Yves; Konstantinov, Igor E.; Berzins, Stuart P.; Rimmelzwaan, Guus F. GND; Turner, Stephen J.; Clemens, E. Bridie; Godfrey, Dale I.; Nguyen, Thi Ho; Kedzierska, Katherine ORCID

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.

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Nüssing, S., Koay, H.-F., Sant, S., Loudovaris, T., Mannering, S.I., Lappas, M., d’Udekem, Y., Konstantinov, I.E., Berzins, S.P., Rimmelzwaan, G.F., Turner, S.J., Clemens, E.B., Godfrey, D.I., Nguyen, T.H., Kedzierska, K., 2019. Divergent SATB1 expression across human life span and tissue compartments. Immunology and cell biology 97, 498–511. https://doi.org/10.1111/imcb.12233
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