Macrophage-specific MHCII expression is regulated by a remote Ciita enhancer controlled by NFAT5

Buxadé Fortuny, Maria; Huerga Encabo, Hector, 1989-; Riera-Borrull, Marta; Quintana-Gallardo, Lucía; López-Cotarelo, Pilar; Tellechea Recarte, Mónica, 1989-; Martínez-Martínez, Sara; Redondo, Juan Miguel; Martín Caballero, Juan; Flores, Juana M.; Bosch Fusté, Elena; Rodríguez-Fernández, José Luis; Aramburu, José (Aramburu Beltrán); López Rodríguez, M. Cristina

doi:http://dx.doi.org/10.1084/jem.20180314

Macrophage-specific MHCII expression is regulated by a remote Ciita enhancer controlled by NFAT5

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Buxadé M, Huerga Encabo H, Riera-Borrull M, Quintana-Gallardo L, López-Cotarelo P, Tellechea M, Martínez-Martínez S, Redondo JM, Martín-Caballero J, Flores JM, Bosch E, Rodríguez-Fernández JL, Aramburu J, López-Rodríguez C. Macrophage-specific MHCII expression is regulated by a remote Ciita enhancer controlled by NFAT5. J Exp Med. 2018; 215(11):2901-2918. DOI 10.1084/jem.20180314

Abstract

MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type-specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of Ciita and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4+ T lymphocytes and attenuated capacity to elicit graft rejection in vivo. Ultrasequencing analysis of NFAT5-immunoprecipitated chromatin uncovered an NFAT5-regulated region distally upstream of Ciita This region was required for CIITA and hence MHCII expression, exhibited NFAT5-dependent characteristics of active enhancers such as H3K27 acetylation marks, and required NFAT5 to interact with Ciita myeloid promoter I. Our results uncover an NFAT5-regulated mechanism that maintains CIITA and MHCII expression in macrophages and thus modulates their T lymphocyte priming capacity.