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Natural cytotoxicity receptor (NCR)+ group 3 innate lymphoid cells (ILC3s), along with (NCR)- ILC3s are two phenotypically distinguishable subsets of ILC3s that have been characterized in mice and humans. In both species, ILC3s are involved in mediating the immune response against specific extracellular pathogens and maintaining tissue homeostasis at mucosal sites, and both (NCR)+ and (NCR)- ILC3s require the transcription factor, ROR gamma t for their development. Following activation, human (NCR)+ ILC3s primarily secrete IL-22 and lymphotoxin alpha/beta, while mouse (NCR)+ ILC3 secrete IL-22, lymphotoxin alpha/beta, TNF-alpha, and varying levels of IFN-gamma. As a result of their similarities with Th22 cells, (NCR)+ ILC3s have been suggested to be the innate equivalent of these cells. In contrast, (NCR)- ILC3s are thought to be the innate counterpart of Th17 cells as these cells primarily secrete IL-17 following activation. ILC3s are activated by IL-1 alpha, IL-1 beta, IL-7, IL-23, TL1A, and Prostaglandin E2 (PGE2). In mice, (NCR)+ ILC3s express NKp46 and lack expression of CCR6, while (NCR)- ILC3s lack expression of NKp46 and are CCR6 positive. In addition to ROR gamma t, most mouse (NCR)+ ILC3s also express the transcription factor, T-bet, and produce IFN-gamma. In contrast to the mouse ILC3 subsets, human (NCR)+ and (NCR)- ILC3s both express CCR6. As a result, these two subsets are typically distinguished from each other based on the expression of NKp44, NKp46, and NCAM-1/CD56 on (NCR)+ ILC3s. In addition, IL-22 production by human ILC3s is primarily restricted to the (NCR)+ ILC3 subset and these cells typically do not express T-bet or produce IFN-gamma. While ILC3s are thought to play a central role in resistance to specific extracellular pathogens, pathogen clearance, and protection of the intestinal epithelial cell barrier, there is also evidence that unregulated activation of these cells may contribute to the pathogenesis of inflammatory bowel disease, obesity-associated airway inflammation, and psoriasis.