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Overall, ILC2s are likely to play a key role in the initiation and propagation of type 2 responses in the lung which may involve crosstalk with conventional T cells

Overall, ILC2s are likely to play a key role in the initiation and propagation of type 2 responses in the lung which may involve crosstalk with conventional T cells. T cells together comprise only a small proportion of the total immune cells in the lung, they have been found to promote lung homeostasis and are emerging as contributors to a variety of chronic lung diseases including pulmonary fibrosis, allergic airway inflammation, and chronic obstructive pulmonary disease (COPD). A particularly intriguing trait of ILCs that has recently emerged is their plasticity and ability to alter their gene expression profiles and adapt their function in response to environmental cues. The malleable nature of these cells may aid in rapid responses to pathogen but may also have downstream pathological consequences. The role of ILC2s in Th2 allergic airway responses is becoming apparent BAY1217389 but the contribution of other ILCs and unconventional T cells during chronic lung inflammation is poorly described. This review presents an overview of our current understanding of the involvement of ILCs and unconventional T cells in chronic pulmonary diseases. or the fungus (10). Notch signaling BAY1217389 has been shown to induce expression and drive IL-13/IL-17 co-producing ILC2 cells during house dust mite induced airway inflammation in mice (40). ILC2s from healthy human donors also express low amounts of RORt and can co-produce IL-13 and IL-22 demonstrating that key functions of ILC2 and ILC3 subsets can co-exist in one cell but appear to be exquisitely balanced by the inflammatory milieu. Human ILC2s activated by IL-1 have been shown to convert into IFN- producing ILC1s by induction of low levels of T-bet and IL-12RII expression (41, 42). IL-12 stimulation BAY1217389 appears to act as a rheostat in directing the ILC1 or ILC2 response, although IL-12 alone is not enough to induce this functional plasticity, a process that can be reversed by exposure to IL-4 (41, 42). In patients with severe COPD, there was elevated IL-12 and an accumulation of IFN-+ ILC2s (43). ILC2 were also shown to upregulate T-bet expression and acquire an ILC1 phenotype in intestinal samples PLAU from Crohn’s disease patients (44). Even in healthy human donors, a small subset of ILC2 cells have the capacity to co-produce IL-13, IFN-, and IL-22 (45, 46). ILC3 and LTi Plasticity Previously, LTi cells were categorized as a subset of ILC3s, although more recent studies have resolved that they are separate populations. Plasticity between the two populations, with the identification of LTi-like ILC3s and the lack of NCR expression on LTi cells that is confounded by its heterogeneous expression on ILC3s, supports the collective discussion of their plasticity. RORt+ ILC3 cells have been shown to co-express T-bet, produce IFN- and differentiate into ILC1 cells in response to inflammation. Purified NKp44+ ILC3s from the murine fetal intestine when cultured with IL-2, IL-23, and IL-1 differentiate into ILC3, however when exposed to IL-2 and IL-12 they acquire the ILC1 phenotype, losing expression of NKp44 and c-kit (47). The switch also appears bi-directional, as IL-2 and IL-23 stimulation of these ILC1 cells, although maintaining expression, caused a significant reduction in the Th1-specific transcription factor T-bet encoded by (47). Human natural killer 22 (NK-22) cells that express IL-22, now defined as ILC3 cells by current nomenclature, have demonstrated similar loss of IL-22 production and acquisition of IFN- expression (48C50). Culturing of tonsillar NK-22 cells, in the presence of IL-2 considerably modified the NK-22 cell cytokine profiles, with IL-2 promoting IFN- secretion and reducing secretion of IL-17 and IL-22 (49). One mechanism driving ILC3 plasticity derives from the levels and availability of the transcription factor T-bet, a critical mediator in lineage commitment of CCR6? RORt+ ILCs. A distinct subset of IL-22 producing ILC3s, which also express NKp46, reside in the gut and develop through T-bet regulation (12, 51). Mice exhibiting loss of T-bet expression through genetic ablation developed CCR6? RORt+ ILC3s but failed to develop NKp46-expressing RORt+ ILCs (NK-22 cells) and could not produce IFN- (51). Environmental cues from commensal microbiota have been shown to be critical in upregulating T-bet expression. Indeed, specific pathogen free (SPF) mice were shown to have greater numbers of T-bet+ NKp46? RORt+ ILC numbers BAY1217389 compared to germ-free mice, with a corresponding decrease in NKp46?CCR6?T-bet?RORt+ ILCs (51). Although studies in the lung during either homeostatic or inflammatory conditions.