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

Foxp3+ regulatory CD4+ T cells (Tregs) induce and maintain tolerance. Tregs co-opt effector or helper T cell (Th) transcription factors to express similar receptors and migrate to Th resident sites to suppress immunity. Treg and Th responses are not perfectly aligned, raising questions about how Tregs are precisely directed to the right location at the right time to suppress immune responses. Specific trafficking is required for Tregs to suppress allograft rejection, so that Tregs sequentially migrate from blood through microvascular endothelium into tissues, and then from tissues through lymphatics to draining lymph nodes (dLN). If lymphatic migration is disrupted, Tregs fail to suppress and instead lose CD25 and Foxp3, becoming pro-inflammatory exTregs. Thus, a major requirement for normal Treg function, and a step not required for Th stability, is lymphatic migration. Our overall hypothesis is that the Treg-lymphatic interaction is an important regulatory nidus, and our goal is to define the key events and structures that regulate this interaction. Specific attributes of Tregs include uniquely high cell surface expression of lymphotoxin DE (LTDE) that stimulates lymphatic endothelial cell (LEC) LTE-receptor (LTER). Receptor stimulation leads to non- canonical NFNB-inducing kinase (NIK) signaling that has numerous effects on LEC structure and function, Treg migration across LEC into lymphatics, and Treg metabolism and stability. Tregs also use PD-1 to stimulate LEC PD-L1, further regulating LEC structure and function and Treg migration. LTER and PD-L1 physically interact and modify each other's signaling. Tregs engage these receptors in fundamentally different ways compared to Th. Further, most tumors express both receptors, and Tregs likewise signal through these receptors to directly regulate tumor growth, invasiveness, and metastases. Thus, the bipartite Treg-LEC and tripartite Treg-LEC-tumor interactions are fundamental sites of regulation for immunity and suppression, applicable to many areas of immune diseases. Since Tregs uniquely deploy specialized receptor-ligand interactions with LECs to regulate many Treg functions, these observations lead to the following specific aims: 1.) Dissect the Treg-LEC interactions that regulate Treg homeostasis, stability, metabolism, and suppression; and 2.) Define LTER and PD-L1 molecular interactions that determine Treg and Th regulation of LECs and tumors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roject Number: 4R37AI062765-22 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Jonathan Bromberg | Institution: UNIVERSITY OF MARYLAND BALTIMORE, BALTIMORE, MD | Award Amount: $559,800 | Activity Code: R37 | Study Section: NSS View on NIH RePORTER: https://reporter.nih.gov/project-details/4R37AI06276522