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Smad7 Controls Immunoregulatory PDL2/1-PD1 Signaling in Intestinal Inflammation and Autoimmunity

Authors :
Lucien P. Garo
Amrendra K. Ajay
Mai Fujiwara
Vanessa Beynon
Chantal Kuhn
Galina Gabriely
Supriya Sadhukan
Radhika Raheja
Stephen Rubino
Howard L. Weiner
Gopal Murugaiyan
Source :
Cell Reports, Vol 28, Iss 13, Pp 3353-3366.e5 (2019)
Publication Year :
2019
Publisher :
Elsevier, 2019.

Abstract

Summary: Smad7, a negative regulator of TGF-β signaling, has been implicated in the pathogenesis and treatment of inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC). Here, we found that Smad7 mediates intestinal inflammation by limiting the PDL2/1-PD1 axis in dendritic cells (DCs) and CD4+T cells. Smad7 deficiency in DCs promotes TGF-β responsiveness and the co-inhibitory molecules PDL2/1 on DCs, and it further imprints T cell-PD1 signaling to promote Treg differentiation. DC-specific Smad7 deletion mitigates DSS-induced colitis by inducing CD103+PDL2/1+DCs and Tregs. In addition, Smad7 deficiency in CD4+T cells promotes PD1 and PD1-induced Tregs in vitro. The transfer of Smad7-deficient CD4+T cells enhances Tregs in vivo and protects against T cell-mediated colitis. Furthermore, Smad7 antisense ameliorates DSS-induced UC, increasing TGF-β and PDL2/1-PD1 signaling. Enhancing PD1 signaling directly via Fc-fused PDL2/1 is also beneficial. Our results identify how Smad7 mediates intestinal inflammation and leverages these pathways therapeutically, providing additional strategies for IBD intervention. : Smad7, a negative regulator of TGF-β signaling, is implicated in the pathogenesis and treatment of inflammatory bowel diseases (IBDs). Here, Garo et al. describe how Smad7 within both dendritic cells and CD4+ T cells limits PD1-mediated Treg induction to promote intestinal inflammation, providing additional therapeutic strategies for IBD intervention. Keywords: Smad7, PD1, PDL1, PDL2, TGF-β, CD103, dendritic cell, DC, Treg, inflammatory bowel disease, IBD, ulcerative colitis, UC

Subjects

Subjects :
Biology (General)
QH301-705.5

Details

Language :
English
ISSN :
22111247
Volume :
28
Issue :
13
Database :
Directory of Open Access Journals
Journal :
Cell Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.6a63f90c1b6740a8a5437c21bd00ecf9
Document Type :
article
Full Text :
https://doi.org/10.1016/j.celrep.2019.07.065