# Regulatory T Cells and Lymphatic Endothelial Cells: Regulatory Interactions for Migration and Suppression

> **NIH NIH R37** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $463,500

## Abstract

Project Summary/Abstract
 Foxp3+ regulatory CD4+ T cells (Treg) induce and maintain tolerance. Treg also limit the tempo
and strength of normal immune responses to environmental antigens and pathogens. How Treg are regulated
to manifest these functions is incompletely understood. Treg co-opt helper T cell (Th) transcription factors to
express similar selected receptors and migrate to Th resident sites to suppress immunity. Since Treg and Th
responses are not precisely aligned, these observations do not fully define mechanisms of how Treg are
regulated, nor identify how their function is channeled to be in the “right place at the right time”.
 The mechanisms of how Treg functions are geographically and kinetically distinct from conventional
CD4+ T cells (Tconv) remain elusive. We demonstrated that specific trafficking is required for Treg to suppress
allograft rejection: Treg sequentially migrate from blood through microvascular endothelium into tissue, and
then from tissue through afferent lymphatics to the draining lymph nodes (dLN). If this sequence is interrupted,
particularly lymphatic migration, Treg fail to be activated and suppress Tconv and dendritic cells (DC) in tissue
and LN. Indeed, Treg lose CD25 and Foxp3, becoming exTreg. Thus, a major requirement for normal Treg
function, and a step not required for Tconv, is afferent lymphatic migration. Our overall hypothesis is that the
Treg-lymphatic interaction is an important regulatory nidus for suppression and tolerance, and our goal is to
define the key events and structures that regulate this interaction.
 Our publications demonstrate novel attributes of Treg migration. Thymus derived (nTreg) and
peripherally induced Treg (iTreg) express high cell surface lymphotoxin  (LT). Treg use LT to migrate
across afferent lymphatic endothelial cells (LEC). Treg LT binds the LEC LT-receptor (LTR) to stimulate
non-canonical NFB-inducing kinase (NIK). NIK signaling facilitates Treg transendothelial migration (TEM) by
inducing LEC responses, including increased CCL21 expression, VCAM-1 rearrangement, and basal
lamellipodia that engage Treg. Our new studies show that the Treg-LEC interaction: 1.) uses LT-LTR to
condition LEC for permissiveness for gating the TEM of other leukocytes (i.e. T, B, DC, M); 2.) determines if
exTreg are induced; and 3.) relies on PD-1(Treg)/PD-L1(LEC) interactions for Treg TEM. Our data
demonstrate novel Treg-LEC interactions that serve essential roles for Treg suppression.
 Since Treg must migrate through tissues and interact with afferent lymphatics, and since Treg uniquely
deploy diverse interactions with LEC that regulate migration and suppression, these observations lead us to
the following specific hypotheses: 1.) Treg-LEC LT-LTR interactions regulate the permissiveness of LEC
for gating TEM of many other leukocyte subsets and acts as a gatekeeper for immunity, suppression, and
resolution of inflammation; 2.) Treg-LEC interactions determine if Treg mai...

## Key facts

- **NIH application ID:** 10115166
- **Project number:** 2R37AI062765-17A1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Jonathan S Bromberg
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $463,500
- **Award type:** 2
- **Project period:** 2004-12-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115166

## Citation

> US National Institutes of Health, RePORTER application 10115166, Regulatory T Cells and Lymphatic Endothelial Cells: Regulatory Interactions for Migration and Suppression (2R37AI062765-17A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10115166. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*