Characterization of phenotype and function of innate lymphoid cells in cutaneous leishmaniasis

利什曼病是一种在皮肤中接种原虫寄生虫后观察到的疾病，会引起从局部自限性皮损到危及生命的内脏的各种症状。针对利什曼原虫的保护性免疫是由感染的树突状细胞(DC)启动的抗原特异性CD8和CD4T细胞介导的。然而，关于耐药性/敏感性的决定是在感染后几天内做出的，这表明先天效应细胞发挥了重要作用。天然淋巴细胞室在保护和调节局部免疫反应中的作用还知之甚少。因此，我们的目标是进一步明确先天性淋巴样细胞(ILCs)和NK细胞在大型乳杆菌感染中的表型和功能。ILC2是皮肤中处于稳定状态的主要ILC亚群，但我们发现，严重感染导致ILC2的丢失，同时诱导感染皮肤中NK细胞和ILC1的激活。在目前的方案中，在详细描述了ILC在感染过程中的频率和表型之后，我们有两个主要的目标：一)表征ILC1和NK细胞激活的机制和相关性；二)研究导致ILC2丢失的机制；三)恢复ILC2在主要病变中的存在，以研究ILC2在感染过程中的作用。ILC2可能对愈合和组织完整性很重要，而ILC1和NK细胞可能有助于适当的Th启动和寄生虫清除。使用生理上相关的低剂量接种，我们的目标是表征ILCs在保护这种重要的人类病原体方面所起的作用。

Leishmaniasis is a disease observed after inoculation of a protozoan parasite into the skin inducing symptoms ranging from local, self-limiting lesions to life-threatening visceralisation. Protective immunity against Leishmania is mediated by antigen specific CD8+ and CD4+ T cells which are primed by infected dendritic cells (DC). However, decisions about resistance/susceptibility are made within a few days post infection suggesting an important role for innate effector cells. The role of the innate lymphocyte compartment for protection and regulation of the local immune response is poorly understood. Therefore, we aim to further define the phenotype and function of innate lymphoid cells (ILCs) and NK cells in L. major infections. ILC2 are the predominant ILC subsets in steady state in skin, however, we found that L. major infection leads to a loss of ILC2s while inducing NK cell and ILC1 activation in the infected skin. In the present proposal, after a detailed characterization of the frequency and phenotype of ILCs during infection, we have two major aims: We plan to i) characterize the mechanisms and relevance of ILC1 and NK cell activation, and ii) to investigate the mechanism leading to ILC2 loss, and iii) to restore the ILC2 presence in L. major lesions in order to examine the role of ILC2 during the course of infection. ILC2 may be important for healing and tissue integrity, whereas ILC1 and NK cells may contribute to proper Th priming and parasite elimination. Using a physiologically relevant low dose inoculum, we aim to characterize the role ILCs play for protection against this important human pathogen.