TY - JOUR
T1 - Interleukin-22 suppresses major histocompatibility complex II in mucosal epithelial cells
AU - Moniruzzaman, Md
AU - Rahman, M. Arifur
AU - Wang, Ran
AU - Wong, Kuan Yau
AU - Chen, Alice C.H.
AU - Mueller, Alexandra
AU - Taylor, Steven
AU - Harding, Alexa
AU - Illankoon, Thishan
AU - Wiid, Percival
AU - Sajiir, Haressh
AU - Schreiber, Veronika
AU - Burr, Lucy D.
AU - McGuckin, Michael A.
AU - Phipps, Simon
AU - Hasnain, Sumaira Z.
PY - 2023/11/6
Y1 - 2023/11/6
N2 - Major histocompatibility complex (MHC) II is dynamically expressed on mucosal epithelial cells and is induced in response to inflammation and parasitic infections, upon exposure to microbiota, and is increased in chronic inflammatory diseases. However, the regulation of epithelial cell-specific MHC II during homeostasis is yet to be explored. We discovered a novel role for IL-22 in suppressing epithelial cell MHC II partially via the regulation of endoplasmic reticulum (ER) stress, using animals lacking the interleukin-22-receptor (IL-22RA1), primary human and murine intestinal and respiratory organoids, and murine models of respiratory virus infection or with intestinal epithelial cell defects. IL-22 directly downregulated interferon-γ-induced MHC II on primary epithelial cells by modulating the expression of MHC II antigen A α (H2-Aα) and Class II transactivator (Ciita), a master regulator of MHC II gene expression. IL-22RA1-knockouts have significantly higher MHC II expression on mucosal epithelial cells. Thus, while IL-22-based therapeutics improve pathology in chronic disease, their use may increase susceptibility to viral infections.
AB - Major histocompatibility complex (MHC) II is dynamically expressed on mucosal epithelial cells and is induced in response to inflammation and parasitic infections, upon exposure to microbiota, and is increased in chronic inflammatory diseases. However, the regulation of epithelial cell-specific MHC II during homeostasis is yet to be explored. We discovered a novel role for IL-22 in suppressing epithelial cell MHC II partially via the regulation of endoplasmic reticulum (ER) stress, using animals lacking the interleukin-22-receptor (IL-22RA1), primary human and murine intestinal and respiratory organoids, and murine models of respiratory virus infection or with intestinal epithelial cell defects. IL-22 directly downregulated interferon-γ-induced MHC II on primary epithelial cells by modulating the expression of MHC II antigen A α (H2-Aα) and Class II transactivator (Ciita), a master regulator of MHC II gene expression. IL-22RA1-knockouts have significantly higher MHC II expression on mucosal epithelial cells. Thus, while IL-22-based therapeutics improve pathology in chronic disease, their use may increase susceptibility to viral infections.
KW - Infectious disease and host defense
KW - Innate immunity and inflammation
KW - Mucosal immunology
UR - http://www.scopus.com/inward/record.url?scp=85170489348&partnerID=8YFLogxK
U2 - 10.1084/jem.20230106
DO - 10.1084/jem.20230106
M3 - Article
C2 - 37695525
AN - SCOPUS:85170489348
SN - 1540-9538
VL - 220
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
M1 - e20230106
ER -