Immunomodulatory roles of lymphatic vessels in allergic airway inflammation

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Project Summary Lymphatic vessels serve as transporters for immune cells, shuttling them together with antigens, cytokines and other factors from peripheral tissues to the draining lymph nodes, where immune responses are shaped. Aside from this transport function, there is emerging evidence, from our lab and others, suggesting that lymphatic vessels may play many other roles in regulating immunity; for example, lymphatic endothelial cells (LECs) can secrete immunosuppressive cytokines and present antigen on MHC class I and II molecules for T cell activa- tion. Lymphatic vessel expansion, or lymphangiogenesis, occurs in allergic airway inflammation associated with asthma, along with many other chronic inflammatory diseases; however, it is unknown how lymphangio- genesis impacts the immunopathology. Using a house dust mite (HDM) mouse model of allergic airway in- flammation, we found that lymphangiogenesis was occurring, indicating that the lymphatic growth factor VEGF- C was upregulated. VEGF-C induced LECs to not only proliferate but also activate CCL21, which recruits na- ïve, regulatory and memory T cell subsets. When we subsequently blocked VEGF-C signaling (with a blocking antibody against its receptor, VEGFR-3) during HDM challenge, we found that these T cell subsets in the lung were reduced, indicating that VEGF-C-activated LECs enhance T cell recruitment and trafficking during allergic airway inflammation and may thereby exacerbate the pathology. On the other hand, our lab recently demon- strated that LECs are able to directly interact with naïve CD4+ T cells, which mediate allergic inflammatory re- sponses, to potentially induce anergy or suppression. In vitro, we found that LECs upregulate MHCII molecules upon inflammatory stimuli and that LEC-T cell interactions can lead to T cell proliferation. To explore the role of direct LEC-CD4+ T cell interactions in vivo, we developed a mouse model with an inducible, LEC-specific MHCII deletion. In preliminary experiments challenging these mice with HDM, we found that the Th2 response was exacerbated at early times, potentially suggesting that MHCII expression by LECs may play immunoregu- latory (i.e., protective) roles in allergic airway inflammation. Taken together, these preliminary findings led us to hypothesize that lymphangiogenesis plays both protective and pathological roles in allergic airway inflamma- tion. To test this, we will 1) Determine the role of VEGF-C signaling during allergic airway inflammation, 2) De- termine the extent to which LECs can directly and indirectly suppress T cell activation and alter differentiation, and 3) Determine if lymphangiogenesis is detrimental in long-term allergic airway inflammation.