TL1A-activated T cells remodel the rectal mucosa in Crohn’s disease patients with perianal fistulizing disease
Abstract
Background
Perianal fistulizing disease (PFD) is a complication that affects about 20% of Crohn’s disease (CD) patients whose etiology remains unknown.
Objectives
To identify predisposing events driving fistula formation.
Design
Rectal biopsies from CD patients with or without PFD (CD+PFD and CD, respectively; n=31) were collected and subjected to single-cell RNA sequencing (scRNA-seq). Functional analyses were conducted using peripheral CD3+ T cells, intestinal tissue explants, primary fibroblasts and 2D-epithelial monolayer cell cultures.
Results
The rectal mucosa of CD+PFD patients is imprinted with cellular and transcriptomic alterations specific to PFD and independent of luminal inflammation, potentially driven by TL1A activation in CD4+ T cells. We identified lymphotoxin beta (LTBor its functional heterotrimer LTα1β2) as a novel mediator downstream of TL1A that, along with IL-22, induces a PFD-associated signature in rectal fibroblast and epithelial cells, respectively. This signature includes an increased abundance of fibroblasts, an induction of matrix-degrading enzymes, transcriptomic rewiring of the lamina propria S1 fibroblasts, and an anti-bacterial and immune responses in epithelial cells. Notably, the induction of LTα1β2and IL-22 occurs independently of TNF signaling, revealing a new TL1A-LTα1β2/IL-22 axis that remains active under anti-TNF therapy.
Conclusion
Our findings revealed unique cellular alterations in the rectum of CD patients with PFD, highlighting the previously unrecognized involvement of TL1A in mediating this signature and supporting the need for exploring the role of TL1A inhibition as a therapeutic approach for PFD.
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