AUTHOR=Jha Atimukta , Ahad Abdul , Mishra Gyan Prakash , Sen Kaushik , Smita Shuchi , Minz Aliva Prity , Biswas Viplov Kumar , Tripathy Archana , Senapati Shantibhushan , Gupta Bhawna , Acha-Orbea Hans , Raghav Sunil Kumar 

TITLE=SMRT and NCoR1 fine-tune inflammatory versus tolerogenic balance in dendritic cells by differentially regulating STAT3 signaling

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.910705

DOI=10.3389/fimmu.2022.910705

ISSN=1664-3224

ABSTRACT=<p>Dendritic cell (DC) fine-tunes inflammatory versus tolerogenic responses to protect from immune-pathology. However, the role of co-regulators in maintaining this balance is unexplored. NCoR1-mediated repression of DC immune-tolerance has been recently reported. Here we found that depletion of NCoR1 paralog SMRT (NCoR2) enhanced cDC1 activation and expression of IL-6, IL-12 and IL-23 while concomitantly decreasing IL-10 expression/secretion. Consequently, co-cultured CD4<sup>+</sup> and CD8<sup>+</sup> T-cells depicted enhanced Th1/Th17 frequency and cytotoxicity, respectively. Comparative genomic and transcriptomic analysis demonstrated differential regulation of IL-10 by SMRT and NCoR1. SMRT depletion represses mTOR-STAT3-IL10 signaling in cDC1 by down-regulating NR4A1. Besides, <italic>Nfkbia</italic> and <italic>Socs3</italic> were down-regulated in <italic>Ncor2</italic> (<italic>Smrt</italic>) depleted cDC1, supporting increased production of inflammatory cytokines. Moreover, studies in mice showed, adoptive transfer of SMRT depleted cDC1 in OVA-DTH induced footpad inflammation led to increased Th1/Th17 and reduced tumor burden after B16 melanoma injection by enhancing oncolytic CD8<sup>+</sup> T-cell frequency, respectively. We also depicted decreased <italic>Ncor2</italic> expression in Rheumatoid Arthritis, a Th1/Th17 disease.</p>