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Abstract Number: 1521

A Novel Gut-joint Migratory TCRab+ Cell Subset Relies on sphingosine-1-phosphate for Tissue Localization

Adam Lefferts1, Emilie Regner2, Eric Norman3, David Claypool4, Hannah Schultz4, Danielle Sansone-Poe4 and Kristine Kuhn5, 1University of Colorado, Anschutz Medical Campus, Aurora, CO, 2University of California San Francisco, San Francisco, CA, 3University of Colorado, Anschutz Medical Campus, Denver, 4University of Colorado, Anschutz Medical Campus, Aurora, 5University of Colorado Anschutz Medical Campus, Aurora, CO

Meeting: ACR Convergence 2020

Keywords: Ankylosing spondylitis (AS), Spondylarthropathies, T Cell

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Session Information

Date: Sunday, November 8, 2020

Session Title: Spondyloarthritis Including Psoriatic Arthritis – Basic Science (1517–1521)

Session Type: Abstract Session

Session Time: 5:00PM-5:50PM

Background/Purpose: Despite findings of similar immune cellular phenotypes in the gut and joint of patients with spondyloarthritis, the mechanistic linkage between intestinal immunology and the subsequent pathogenic targeting of the enthesis by gut-originating cells have not been defined.  Prior work in our lab demonstrated a correlation between the numbers of colon intraepithelial lymphocytes (IELs) and circulating lymphocytes, leading us to hypothesize that IELs migrate from the colon to the enthesis as one mechanistic link between the colon and joint.

Methods: We used the KikGR transgenic mouse in which colonoscopy guided violet light allows labeling of cells in the distal colon, termed photo-conversion. Following photo-conversion, we evaluated the Achilles enthesis for the presence and characteristics of labeled cells by flow cytometry in two models: the TNFDARE model of spontaneous inflammatory bowel disease and arthritis and hock injection of complete Fruend’s adjuvant (CFA). IEL recruitment to the colon epithelium was evaluated using microarray and confirmed by qPCR, the pan spingosine-1-phosphate receptor (S1PR) antagonist FTY720 to interrupt cellular trafficking, and LysM-Cre x MyD88fl/fl mice.

Results: Following photo-conversion of the distal colon, we identified colon-labeled CD3+TCRab+ cells in the Achilles enthesis within 72 hours. The numbers of trafficked T cells significantly increased in the entheses during inflammation caused by either CFA or in TNF DARE mice compared to non-arthritic controls; however, the percentage of gut-derived cells remained at ~10% regardless of the presence of arthritis. Following this discovery, we hypothesized that the function of IELs may be affected by their interactions in the gut. Therefore, we investigated how IELs localize and interact with the colon epithelium. By microarray and qPCR, we identified that the trafficking receptor S1PR1 was significantly expressed on IELs compared to lamina propria T cells. The S1PR inhibitor FTY720 blocked IEL localization to the colon epithelium, and gut-joint trafficking was ablated. Finally, we identified that MyD88 expression by myeloid cells was critical for IEL localization via S1P, and treatment of bone marrow derived dendritic cells (BMDCs) with cecal contents induces sphk1 expression in a MyD88 dependent fashion, which was sufficient to induce T cell migration in an S1P-dependent fashion.

Conclusion: Altogether, our data demonstrate a model of gut-joint trafficking. Bacterial signals through MyD88 in myeloid cells stimulate the S1P pathway to recruit IELs to the colon epithelium. Although the specific interaction with the epithelium and impact on T cells is yet to be elucidated, we hypothesize that this interaction functionally alters IELs. The colon IELs then traffic to the joint, where their role in inflammation likely depends upon the functional programming they receive in the intestine. These findings may shed light into pathogenic mechanisms connecting the gut and joint in spondyloarthritis.


Disclosure: A. Lefferts, None; E. Regner, None; E. Norman, None; D. Claypool, None; H. Schultz, None; D. Sansone-Poe, None; K. Kuhn, None.

To cite this abstract in AMA style:

Lefferts A, Regner E, Norman E, Claypool D, Schultz H, Sansone-Poe D, Kuhn K. A Novel Gut-joint Migratory TCRab+ Cell Subset Relies on sphingosine-1-phosphate for Tissue Localization [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/a-novel-gut-joint-migratory-tcrab-cell-subset-relies-on-sphingosine-1-phosphate-for-tissue-localization/. Accessed January 21, 2021.
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