Immunomodulatory roles of lymphatic vessels in allergic airway inflammation

项目摘要 淋巴管充当免疫细胞的转运体，将它们与抗原、细胞因子和免疫球蛋白一起穿梭。 从外周组织到引流淋巴结的其他因素，在那里形成免疫反应。一边 从这种运输功能，有新的证据，从我们的实验室和其他人，表明淋巴 血管在调节免疫方面可能发挥许多其他作用;例如，淋巴管内皮细胞（LECs）可以 分泌免疫抑制性细胞因子并在MHC I类和II类分子上呈递抗原以激活T细胞， 是的。淋巴管扩张，或淋巴管生成，发生在过敏性气道炎症相关 哮喘，沿着许多其他慢性炎症性疾病;然而，淋巴管- 遗传影响免疫病理学。使用屋尘螨（HDM）小鼠过敏性气道模型， 炎症时，我们发现淋巴管生成正在发生，表明淋巴管生长因子VEGF- C被上调。VEGF-C诱导LEC不仅增殖，而且还激活CCL21，CCL21招募na- 调节和记忆T细胞亚群。当我们随后阻断VEGF-C信号传导时（用阻断剂）， 在HDM攻击期间，我们发现肺中的这些T细胞亚群 减少，表明VEGF-C激活的LEC在过敏性疾病中增强T细胞的募集和运输。 气道炎症，并因此可能加重病理。另一方面，我们的实验室最近恶魔- 证明LEC能够直接与介导过敏性炎症反应的幼稚CD4 + T细胞相互作用。 sponses，潜在地诱导无反应性或抑制。在体外，我们发现LEC上调MHCII分子， 在炎症刺激后，LEC-T细胞相互作用可导致T细胞增殖。探究的作用 直接LEC-CD4 + T细胞在体内的相互作用，我们开发了一种小鼠模型，具有可诱导的，LEC特异性 MHCII缺失。在用HDM攻击这些小鼠的初步实验中，我们发现Th2应答 在早期加重，可能表明LEC表达MHCII可能在免疫调节中起作用。 延迟的（即，保护）在过敏性气道炎症中的作用。综上所述，这些初步发现使我们 假设淋巴管生成在过敏性气道炎症中起保护作用和病理作用， 是的。为了验证这一点，我们将1）确定VEGF-C信号传导在过敏性气道炎症中的作用，2） 确定LEC可以直接和间接抑制T细胞活化和改变分化的程度， 和3）确定淋巴管生成在长期过敏性气道炎症中是否有害。

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.