The Origin and Role of Pulmonary ILC2 Subsets in Anti-Helminth Immunity

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Project Summary The World Health Organization estimates that soil transmitted helminths infect 1 in 4 people worldwide. Protection or clearance of these parasitic worms requires the initiation of a type-2 immune response. Productive type-2 immunity and worm clearance are dependent on three key cytokines: interleukin (IL)-4, IL-5, and IL-13. Group 2 innate lymphoid cells (ILC2) represent an important source of type-2 cytokines. Specifically, ILC2 cells sense damaged mucosa and act as early orchestrators anti-helminth immunity. Currently, much of our understanding regarding the role of ILC2 cells in anti-helminth immunity stems from work focused on tissue- resident ILC2 or natural ILC2 (nILC2) cells. However, we and others have recently described a second subset of migratory ILC2s, termed inflammatory ILC2, (iILC2) cells. The distinct phenotype, timing, origin, and function of these distinct ILC2 subsets suggests that iILC2 cells serve a unique role in anti-helminth immunity. The studies outlined herein will address the following critical gaps in our knowledge: 1) The origin(s) of iILC2 cells, which remains in debate. 2) How iILC2 cells transit to the lung and the extent they enter the parenchyma during infection is unknown. 3) The impact that iILC2 cells have on tissue-resident ILC2 population remains unclear, and their role in long-term protection against helminths has not been explored. The aims below will address these knowledge gaps by testing the central hypothesis that migratory iILC2 cells, originating from small intestine or bone marrow precursors, acquire an nILC2 phenotype upon entry into the lung and contribute significantly to barrier immunity after repeated helminth infection. Aim 1: Determine iILC2 origin and tissue heterogeneity during helminth infection. Aim 2: Elucidate the mechanism of iILC2 migration and diapedesis into the lung. Aim 3: Determine the extent that iILC2 cells contribute to the tissue-resident ILC2 pool after sequential N. brasiliensis exposure. These aims are both innovative in concept (by challenging the current dogma surrounding iILC2 cells) and approach (by using unique reporter mice and genomic systems to track the fate and function of iILC2 cells). This proposal is significant because understanding of the origin of iILC2 cells, how they egress and migrate to inflamed mucosa, and their contribution to the long-term tissue-resident ILC2 population in the lung significantly advances our understanding of ILC2 biology. Filling these key gaps in our knowledge will establish the role of iILC2 cells as both critical first responders to helminth infection and also identify the mechanisms contributing to their role in long-term barrier maintenance and integrity.