NFATc1 induction by an intronic enhancer restricts NKT γδ cell formation

Sabrina Giampaolo; Cristina M Chiarolla; Konrad Knöpper; Martin Vaeth; Matthias Klein; Azeem Muhammad; Tobias Bopp; Friederike Berberich-Siebelt; Amiya K Patra; Edgar Serfling; Stefan Klein-Hessling

doi:10.1016/j.isci.2023.106234

NFATc1 induction by an intronic enhancer restricts NKT γδ cell formation

iScience. 2023 Feb 19;26(3):106234. doi: 10.1016/j.isci.2023.106234. eCollection 2023 Mar 17.

Authors

Affiliations

¹ Institute of Pathology, Julius Maximilians University Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
² Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
³ Institute for Immunology, University Medical Center, University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.
⁴ Peninsula Medical School, University of Plymouth, The John Bull Building, Plymouth Science Park, Research Way, Plymouth PL6 8BU, UK.
⁵ Comprehensive Cancer Center Mainfranken, Würzburg, Germany.

Abstract

In thymus, the ablation of T cell receptor (TCR)-activated transcription factor NFATc1 or its inducible isoforms during the double-negative (DN) stages of thymocyte development leads to a marked increase in γδ thymocytes whereas the development of αβ thymocytes remains mostly unaffected. These γδ thymocytes are characterized by the upregulation of the promyelocytic leukemia zinc-finger factor (PLZF), the "master regulator" of natural killer T (NKT) cell development, and the acquisition of an NKT γδ cell phenotype with higher cell survival rates. The suppressive function of NFATc1 in NKT γδ cell formation critically depends on the remote enhancer E2, which is essential for the inducible expression of NFATc1 directed by its distal promoter P1. Thus, the enhancer deciphers a strong γδ TCR signal into the expression of inducible NFATc1 isoforms resulting in high levels of NFATc1 protein that are essential to control the numbers of NKT γδ cells.

Keywords: Immunology; developmental biology; molecular biology.