Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

Abstract

Until recently, the known roles of lymphatic endothelial cells (LECs) in immune modulation were limited to directing immune cell trafficking and passively transporting peripheral Ags to lymph nodes. Recent studies demonstrated that LECs can directly suppress dendritic cell maturation and present peripheral tissue and tumor Ags for autoreactive T cell deletion. We asked whether LECs play a constitutive role in T cell deletion under homeostatic conditions. In this study, we demonstrate that murine LECs under noninflamed conditions actively scavenge and cross-present foreign exogenous Ags to cognate CD8+ T cells. This cross-presentation was sensitive to inhibitors of lysosomal acidification and endoplasmic reticulum–golgi transport and was TAP1 dependent. Furthermore, LECs upregulated MHC class I and the PD-1 ligand PD-L1, but not the costimulatory molecules CD40, CD80, or CD86, upon Ag-specific interactions with CD8+ T cells. Finally, Ag-specific CD8+ T cells that were activated by LECs underwent proliferation, with early-generation apoptosis and dysfunctionally activated phenotypes that could not be reversed by exogenous IL-2. These findings help to establish LECs as APCs that are capable of scavenging and cross-presenting exogenous Ags, in turn causing dysfunctional activation of CD8+ T cells under homeostatic conditions. Thus, we suggest that steady-state lymphatic drainage may contribute to peripheral tolerance by delivering self-Ags to lymph node–resident leukocytes, as well as by providing constant exposure of draining peripheral Ags to LECs, which maintain tolerogenic cross-presentation of such Ags.

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

“…24 Furthermore, tumor-associated LECs may directly cross-present tumor antigens to CD8 + T cells and render them dysfunctional in the tumor microenvironment. 25 , 26 LECs can also inhibit the maturation of dendritic cells, 27 secrete inhibitory molecules such as indoleamine 2,3-dioxygénase (IDO), inducible nitric oxide synthase (iNOS) and transforming growth factor beta (TGF-β), and impair T cell activation through expression of inhibitory receptor ligands (e.g. programmed cell death ligand 1 and 2 (PD-L1 and 2)).…”

Immunomodulatory Roles of Lymphatic Vessels in Cancer Progression

“…Large or opsonized antigens are taken up by subcapsular macrophages, whereas smaller antigens flow into small conduits lined with follicular DCs in which they can be taken up directly by antigen-specific B cells (21). On the other hand, LECs have access to all lymph-borne antigens, and it was recently shown that LECs can actively scavenge these antigens, process them intracellularly, and cross-present them to T cells for deletional tolerance (22,23), which is discussed in more detail later. Furthermore, LECs can retain antigen for long periods of time and may play a role in recalling memory T cells (24).…”

“…Second, LECs (as well as FRCs) constitutively express and present self-antigen on MHC class I molecules to delete autoreactive T cells and thus help maintain peripheral tolerance to these self-antigens (37,38). Third, as mentioned above, it is now known that LECs can actively scavenge exogenous lymph-borne antigens and process them for cross-presentation on MHC class I molecules (22,23). Because LECs lack costimulatory molecules necessary to activate effector CD8 T cells, and instead they express high levels of the inhibitory ligand PD-L1 (39), LEC presentation of the peptide-MHC class I complex can drive deletional tolerance of na€ ve CD8 T cells (22,23).…”

“…Third, as mentioned above, it is now known that LECs can actively scavenge exogenous lymph-borne antigens and process them for cross-presentation on MHC class I molecules (22,23). Because LECs lack costimulatory molecules necessary to activate effector CD8 T cells, and instead they express high levels of the inhibitory ligand PD-L1 (39), LEC presentation of the peptide-MHC class I complex can drive deletional tolerance of na€ ve CD8 T cells (22,23). Even though the relative importance of exogenous antigen presentation by LECs in the context of DCs and other antigen-presenting cells is not known, it is likely to have interesting new implications in our understanding of tumor immunity, and may constitute a major reason why lymphangiogenesis in the tumor margin or DLN is positively correlated with metastasis.…”

Engineering opportunities in cancer immunotherapy

“…Tumor-draining LNs contain both tumor antigen-primed T cells with up-regulated checkpoint molecules and immune cells with up-regulated checkpoint ligands (36). LN-resident DCs can induce tolerance in CD8 + T cells, and LN stromal cells can play similar roles (77)(78)(79)(80). These factors suggest that the tumor-draining LN may contain important biomarkers relevant to diagnosis.…”