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Arginase-I expression by innate lymphoid cells during fetal development, adult homeostasis, and inflammation


Innate lymphoid cells (ILCs) are a family of immune cells involved in development, homeostasis, and the host response to pathogens. In order to identify subsets of these cells in situ and genetically target them, additional markers for ILCs need to be established. Here, I demonstrate that arginase-I (Arg1), a urea cycle enzyme induced in alternatively activated macrophages, is expressed by multiple ILC lineages in the fetal and adult mouse. In the adult lung, group 2 ILCs (ILC2s) express Arg1 at rest and during type 2 inflammation induced by the parasitic helminth Nippostrongylus brasiliensis. While macrophages induce Arg1 through STAT6 activation, ILC2s express Arg1 in a STAT6-independent manner. Total numbers of Arg1+ cells in the lung are regulated by IL-33, which elevates ILC2 numbers and indirectly induces Arg1 expression in macrophages through activation of STAT6. Arg1 expression in ILC2s may provide a way to target these cells without altering T cell responses.

In fetal development, specialized members of group 3 ILCs (ILC3s), lymphoid tissue inducer (LTi) cells, are required for lymph node and Peyer's patch organogenesis, but how LTi cells develop at these sites remains unclear. Here, we identify an Arg1+, Id2+ ILC population in the fetal intestine that can differentiate into IL-7Rα+NK1.1+T-bet+ group 1 ILCs (ILC1s), GATA3hi ILC2s, and RORγt+ group ILC3s in vitro. Based on transcription factor expression, ILC precursors in the fetal intestine represent an intermediate developmental stage between T-bet RORγt- ILC precursors and differentiated ILC lineages. These ILC precursors outnumber other innate lymphoid populations in the intestine at embryonic day (E) 13.5. At E16.5, after the initiation of Peyer's patch organogenesis, intestinal ILC precursors accumulate at the Peyer's patch anlage in a manner that is dependent on lymphotoxin-α (LTα). Thus, during development, ILC precursors accumulate in the intestine, where they aggregate at sites of lymphoid tissue organogenesis and differentiate into mature ILC lineages.

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