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Lymphotoxin Beta Receptor Classical NFkB Signaling in Lymphatic Endothelial Cells Drives Treg Tissue Stability

V. Saxena1, W. Piao1, L. Li1, M. W. Shirkey1, R. Lakhan1, S. Walden2, K. L. Hippen2, B. Blazar2, J. S. Bromberg1

1University of Maryland School of Medicine, Baltimore, MD, 2University of Minnesota, Minneapolis, MN

Meeting: 2022 American Transplant Congress

Abstract number: 482

Keywords: Endothelial cells, Graft survival, Mice, knockout, T cells

Topic: Basic Science » Basic Science » 09 - Signaling and Co-Stimulation

Session Information

Session Name: Antigen Presentation and Costimulation

Session Type: Rapid Fire Oral Abstract

Date: Tuesday, June 7, 2022

Session Time: 3:30pm-5:00pm

 Presentation Time: 3:40pm-3:50pm

Location: Hynes Room 309

*Purpose: Regulatory T cell (Treg) suppressor function and allograft protection depend on maintenance of transcription factor Foxp3 expression and lymphatic migration, respectively. Treg lymphotoxin (LT) αβ signals LTβ receptor (LTβR) on lymphatic endothelial cells (LEC). We tested the hypothesis that LTαβ-LTβR signaling specifically regulates Treg stability, migration, and suppressor function.

*Methods: Treg stability, migration and function were analyzed in vitro in a transwell based LEC migration assay and in vivo in islet allograft and footpad migration models. Mice with deletion of LTα-/-, LTβR-/-, and Prox1-Cre-ERT2+/-LTβRfl/fl (KOfl) in which LTβR is deleted in LEC by tamoxifen treatment, were used. Tregs were analyzed by immunofluorescence microscopy and flow cytometry.

*Results: Treg maturation and execution of suppressor function depends on sequential migration from the target tissue to the draining lymph nodes (dLN). Treg LTα1β2 stimulates LTβR on LEC during afferent lymphatic migration. Disruption of Treg-LEC interactions resulted in impaired islet allograft survival from 25d to 13d in KOfl mice (p<.03), to 15d in LTβR-/- mice (p<.03), and to 13d in mice receiving LTα-/- Treg (p<.03). Conditional or germline deletion of LTβR on LEC, or deletion of LTα on Treg, led to Treg retention in the graft and poor migration from tissues to the dLN. Non-migrating Tregs were converted to Foxp3loCD25lo exTreg. In a transwell based Treg-LEC co-culture assay, the non-migrating Tregs became exTregs and were accompanied by increased methylation at the Foxp3 locus and decreased suppressor function. An LTβR decoy peptide blocking classical, but not non-classical LTβR NFκB signaling, prevented conversion to exTregs. Since LEC LTβR stimulates the NFκB classical pathway to increase IL-6 secretion, both neutralization of IL-6 with antibody or decoy peptide blockade of classical LTβR NFκB inhibited IL-6 and prevented conversion of Treg to exTreg. Role of classical LTβR NFκB was confirmed with human Tregs migrating across human LEC.

*Conclusions: Treg LTαb and LEC LTβR interactions are important for Treg migration, stability, and suppressor function. Disruption of the interactions results in poor migration, increased retention in the graft, loss of Foxp3 expression, and thereby the ability to protect the allograft. The exTreg have the potential to become T effector cells and cause allograft rejection. ExTreg conversion can be prevented therapeutically by inhibiting IL-6 or by blocking classical LTβR NFκB.

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To cite this abstract in AMA style:

Saxena V, Piao W, Li L, Shirkey MW, Lakhan R, Walden S, Hippen KL, Blazar B, Bromberg JS. Lymphotoxin Beta Receptor Classical NFkB Signaling in Lymphatic Endothelial Cells Drives Treg Tissue Stability [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/lymphotoxin-beta-receptor-classical-nfkb-signaling-in-lymphatic-endothelial-cells-drives-treg-tissue-stability/. Accessed May 28, 2025.

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