Neuroprotective protein ADNP-dependent histone remodeling complex promotes T helper 2 immune cell differentiation

• Published in: Immunity (Cambridge, Mass.) Mass.), 2023-07, Vol.56 (7), p.1468-1484.e7
• Main Authors: Ferreira, Ana C.F., Szeto, Aydan C.H., Clark, Paula A., Crisp, Alastair, Kozik, Patrycja, Jolin, Helen E., McKenzie, Andrew N.J.
• Format: Article
• Language: English
• Subjects: ADNP; AP-1; asthma; Cell Differentiation; Cytokines - metabolism; GATA3; GATA3 Transcription Factor - genetics; GATA3 Transcription Factor - metabolism; Gene Expression Regulation; histone remodeling; Histones - metabolism; IL-13; immunity; T helper 2 cells; Th2; Th2 Cells; Transcription Factors - genetics; Transcription Factors - metabolism; type 2 cytokines
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2023.05.010

Type 2 immune responses are critical in tissue homeostasis, anti-helminth immunity, and allergy. T helper 2 (Th2) cells produce interleukin-4 (IL-4), IL-5, and IL-13 from the type 2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand transcriptional regulation of Th2 cell differentiation, we performed CRISPR-Cas9 screens targeting 1,131 TFs. We discovered that activity-dependent neuroprotector homeobox protein (ADNP) was indispensable for immune reactions to allergen. Mechanistically, ADNP performed a previously unappreciated role in gene activation, forming a critical bridge in the transition from pioneer TFs to chromatin remodeling by recruiting the helicase CHD4 and ATPase BRG1. Although GATA3 and AP-1 bound the type 2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type 2 cytokine expression. Our results demonstrate an important role for ADNP in promoting immune cell specialization. [Display omitted] •CRISPR screen identifies ADNP-mediated regulation of type 2 cytokine expression•ADNP is required to promote type 2 cytokine production•ADNP recruits the CHD4-BRG1 complex to remodel chromatin at the Th2 cytokine locus•ADNP-deficient mice display impaired antigen-specific Th2 cell responses Th2 cells orchestrate type 2 immune responses by producing specific cytokines, but the mechanism underlying their regulation is not fully understood. Ferreira et al. discover that the neuroprotective protein ADNP is required for effective IL-13 production by Th2 cells and is indispensable for immune reactions to allergens.