Shaping of Peripheral T Cell Responses by Lymphatic Endothelial Cells

Abstract

Lymph node stromal cells (LNSCs) have newly been promoted to the rank of new modulators of T cell responses. The different non-hematopoietic cell subsets in lymph node (LN) were considered for years as a simple scaffold, forming routes and proper environment for antigen (Ag)-lymphocyte encountering. Deeper characterization of those cells has recently clearly shown their impact on both dendritic cell and T cell functions. In particular, lymphatic endothelial cells (LECs) control lymphocyte trafficking and homeostasis in LNs and limit adaptive immune responses. Therefore, the new role of LECs in shaping immune responses has drawn the attention of immunologists. Striking is the discovery that LECs, among other LNSCs, ectopically express a large range of peripheral tissue-restricted Ags (PTAs), and further present PTA-derived peptides through major histocompatibility class I molecules to induce self-reactive CD8+ T cell deletional tolerance. In addition, both steady-state and tumor-associated LECs were described to be capable of exogenous Ag cross-presentation. Whether LECs can similarly impact CD4+ T cell responses through major histocompatibility class II restricted Ag presentation is still a matter of debate. Here, we review and discuss our current knowledge on the contribution of Ag-presenting LECs as regulators of peripheral T cell responses in different immunological contexts, including autoimmunity and cancer.

Postpartum Involution and Cancer: An Opportunity for Targeted Breast Cancer Prevention and Treatments?

“…Histologic evidence confirms the presence of increased lymphatic associated macrophages in PPBC patients (51). Molecular analysis of the lymphatic vessels and macrophages during involution and in models of PPBC has also revealed expression of programmed death ligand-1 (PD-L1), similar to what is observed during peripheral tolerance (60)(61)(62)(63). Since PD-L1 engagement of its receptor PD-1 inhibits T cell responses through activation of pro-apoptotic signaling, these data suggest that lymphatic-mediated immune avoidance (64-66) is one mechanism by which involution promotes PPBC.…”

The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors

“…Even if T cells are successfully activated against tAgs, proliferate, and leave LNs for systemic dissemination, upon their exit through efferent lymphatic vessels, they can be "tolerized" by the binding of programmed death 1 (PD-1) receptor upregulated on activated T cells, with its ligand (PD-L1) expressed on lymphatic endothelial cells (LECs) [56][57][58]. In manners that are not yet completely characterized, LECs can variably express signaling machinery for Ag presentation and co-inhibitory signaling to "tolerize" cells [59][60][61][62]. As a consequence, the lymphatics, typically a site for initiating anti-tumor immune responses, can also be a site for initiating immune tolerance to cancer.…”

Abnormal lymphatic vessel development is associated with decreased decidual regulatory T cells in severe preeclampsia

“…26 Last, but most importantly, lymphatics play an important role in the regulation of adaptive immunity and tolerance through lymphocyte and antigen-presenting cell trafficking and transmigration. 33 LECs also express MHC II molecules, which cooperate with dendritic cells and may play a role in CD4 T-cell tolerance. The transport role of the lymphatics, including cell transmigration, trafficking, and antigen presentation, is understood to be needed for the maintenance of immune tolerance.…”

“…27,28 In fact, lymphatics are present in immunologically privileged organs including T-cell tolerance. 33 LECs also express MHC II molecules, which cooperate with dendritic cells and may play a role in CD4 T-cell tolerance. 28,34 Additionally, antigen-presenting cells that migrate through lymphatic vessels interact with naive T cells in the draining lymph Maternal-fetal immune privilege is pivotal in the maintenance of pregnancy to term.…”