NFATc1 induction by an intronic enhancer restricts NKT γδ cell formation

• Published in: iScience Vol. 26; no. 3; p. 106234
• Main Authors: Giampaolo, Sabrina, Chiarolla, Cristina M., Knöpper, Konrad, Vaeth, Martin, Klein, Matthias, Muhammad, Azeem, Bopp, Tobias, Berberich-Siebelt, Friederike, Patra, Amiya K., Serfling, Edgar, Klein-Hessling, Stefan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.03.2023; Elsevier
• Subjects: developmental biology; Immunology; molecular biology; molecular biology; developmental biology; Immunology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.106234

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. [Display omitted] •Ablation of NFATc1 leads to the expansion of PLZF+ NK γδ thymocytes•High levels of NFATc1 in γδ thymocytes depend on the activity of the E2 enhancer•The inducible form NFATc1/α enforces cell death of NK γδ thymocytes Molecular biology; Immunology; Developmental biology