An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19.

BioRxiv : the Preprint Server for Biology
R. McGregorBehdad Afzali

Abstract

Pro-inflammatory immune responses are necessary for effective pathogen clearance, but cause severe tissue damage if not shut down in a timely manner 1,2 . Excessive complement and IFN-γ-associated responses are known drivers of immunopathogenesis 3 and are among the most highly induced immune programs in hyper-inflammatory SARS-CoV2 lung infection 4 . The molecular mechanisms that govern orderly shutdown and retraction of these responses remain poorly understood. Here, we show that complement triggers contraction of IFN-γ producing CD4 + T helper (Th) 1 cell responses by inducing expression of the vitamin D (VitD) receptor (VDR) and CYP27B1, the enzyme that activates VitD, permitting T cells to both activate and respond to VitD. VitD then initiates the transition from pro-inflammatory IFN-γ + Th1 cells to suppressive IL-10 + Th1 cells. This process is primed by dynamic changes in the epigenetic landscape of CD4 + T cells, generating superenhancers and recruiting c-JUN and BACH2, a key immunoregulatory transcription factor 5-7 . Accordingly, cells in psoriatic skin treated with VitD increased BACH2 expression, and BACH2 haplo-insufficient CD4 + T cells were defective in IL-10 production. As proof-of-concept, we show that CD4 + T...Continue Reading

Citations

Datasets Mentioned

BETA
GSE145926
GSE122960
GSE119416
GSE45975

Methods Mentioned

BETA
RNAseq
bronchoalveolar lavage
scRNAseq
biopsies
scRNA-seq
protein array
acetylation
histone acetylation
ChIP-seq
RNA-seq

Related Concepts

Related Feeds

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.

Related Papers

International Journal of Immunopathology and Pharmacology
S EspositoN Principi
International Journal of Clinical Practice
Andrius Bleizgys
© 2021 Meta ULC. All rights reserved