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

About This Grant

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 􀁄􀁅 (LT􀁄􀁅) that stimulates lymphatic endothelial cell (LEC) LT􀁅-receptor (LT􀁅R). Receptor stimulation leads to noncanonical NF􀁎B-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. LT􀁅R 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 LT􀁅R and PD-L1 molecular interactions that determine Treg and Th regulation of LECs and tumors.