Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: To induce tolerance, regulatory T cells (Treg) are required to migrate from tissues via afferent lymphatic vessels (LV) to the draining lymph node (dLN). To do so, Treg lymphotoxin alpha (LTα) stimulates lymphotoxin beta-receptor (LTβR) signaling on lymphatic endothelial cells (LEC). We hypothesized that LEC LTβR drives changes in LN structure and function important for Treg migration and suppressive function.
*Methods: Prox1-Cre-ERT2 mice were crossed with LTβRfl/fl mice to generate Prox1-Cre-ERT2+/-LTβRfl/fl (KO) mice, which lack LTβR expression in LEC only after tamoxifen treatment. Littermate Prox1-Cre-ERT2-/-LTβRfl/fl (WT) were used as controls. Using flow cytometry, immunohistochemistry and in vivo migration assays, the effects of LTβR depletion on Treg lymphatic migration and LN structures were analyzed.
*Results: In Cre-Lox mice, 10 days after tamoxifen treatment, LTβR expression was markedly reduced specifically on LEC, yet maintained in fibroblastic reticular cells and blood vessel endothelial cells. LTβR depletion did not affect LN architecture, but reduced accumulation of Foxp3+ cells in LN cortical ridge, the LN microdomain important for Treg induction. LTβR depletion was accompanied by decreased expression of CXCL12 and CCL21, chemokines important for T cell migration, while expression of VCAM-1, ICAM-1, and CCL19 remained similar to WT. LTβR depletion also reduced expression of non-canonical NFκB kinase and the chemotactic lipid sphingosine-1-phosphate in LEC. This selective inhibition resulted in poor Treg migration in KO mice from tissues to dLN. These effects were confirmed in an islet allograft model, where Treg transferred into the graft migrated poorly to the dLN in KO mice and resulted in reduced allograft survival from 25d to 13d (p<.03). Migrating Treg maintained high Foxp3 expression, while non-migrating Treg lost Foxp3 and CD25 expression to become exTreg.
*Conclusions: LTβR depletion from LEC inhibited Treg migration from tissues to LN and reduced accumulation of Foxp3+ Treg in the LN. Non-migrating Treg became exTreg and correlated with poor islet allograft survival. LTβR was identified as a key regulator of Treg migration and function and subsequently graft survival.
To cite this abstract in AMA style:Saxena V, Piao W, Li L, Xiong Y, Palusckievicz CC, Simon T, Shirkey MW, Abdi R, Bromberg JS. Lymphotoxin Beta Receptor Regulates Draining Lymph Node Structure and Treg Migration [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/lymphotoxin-beta-receptor-regulates-draining-lymph-node-structure-and-treg-migration/. Accessed December 5, 2020.
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