Exhausted-like Group 2 Innate Lymphoid Cells in Chronic Allergic Inflammation

Mammalian group 2 innate lymphoid cells (ILC2s) initiate early immune responses against an allergen. ILC2s are not functionally uniform or stable, especially when they receive stimulation. ILC2s acquire a memory-like phenotype upon activation via interleukin (IL)-33 or an allergen. Activation by IL-25 provides ILC2s with a capacity to produce IL-17 similar to that of ILC3s. IL-1β and IL-12 enable ILC2s to produce interferon (IFN)γ, an ILC1 cytokine. A small population of ILC2s express certain ‘exhaustion’ markers and show low reactivity in models of chronic or severe inflammation. Such hyporesponsive ILC2s have been tentatively designated as exhausted-like ILC2s. Transcription factor Runx family members can suppresses the induction of exhausted-like ILC2s during chronic or severe airway allergy in mice. Mammalian group 2 innate lymphoid cells (ILC2s) are responsible for the early production of type 2 cytokines at mucosal barriers upon exposure to allergen. Inflammatory tissue environmental cues can influence ILC2 activity, and this cellular population can be further categorized into subtypes with additional or alternative functions. Subtypes can include trained (or ‘memory-like’) ILC2s, which recall previous allergic inflammation, inflammatory ILC2s, which acquire the ability to produce IL-17, and ex-ILC2s, which produce ILC1 cytokines. However, the functional states of ILC2s at sites of chronic or severe inflammation are not well characterized. Here, we discuss the emergence of ILC2s with ‘exhausted’-like signatures, and argue that their hyporesponsiveness to stimulation and expression of inhibitory receptors is relevant in mammalian chronic allergic inflammation. Mammalian group 2 innate lymphoid cells (ILC2s) are responsible for the early production of type 2 cytokines at mucosal barriers upon exposure to allergen. Inflammatory tissue environmental cues can influence ILC2 activity, and this cellular population can be further categorized into subtypes with additional or alternative functions. Subtypes can include trained (or ‘memory-like’) ILC2s, which recall previous allergic inflammation, inflammatory ILC2s, which acquire the ability to produce IL-17, and ex-ILC2s, which produce ILC1 cytokines. However, the functional states of ILC2s at sites of chronic or severe inflammation are not well characterized. Here, we discuss the emergence of ILC2s with ‘exhausted’-like signatures, and argue that their hyporesponsiveness to stimulation and expression of inhibitory receptors is relevant in mammalian chronic allergic inflammation. binding partner of either Runx1, Runx2, or Runx3. CD4+ helper T cells other than Foxp3+ regulatory T cells. epigenetic modification that generally marks active enhancers. subtype of IL-25-activated ILC2s with the capacity to produce IL-17. cytokine that recruits eosinophils and activates B cells in allergic inflammation. cytokine that has immunosuppressive functions via STAT3 activation. cytokine that mediates allergic inflammation or induces goblet cell hyperplasia, mucus hypersecretion, and airway hyperresponsiveness. group 1 helper ILCs; produce type 1 cytokines, IFNγ and TNFα. group 2 helper ILCs; produce type 2 cytokines, IL-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and amphiregulin; form an ILC subset that is abundant in the lung and involved in airway allergic immune reactions. group 3 helper ILCs; produce type 3 cytokines, IL-17 and IL-22. lymphoid cells that do not express any antigen-recognition receptors. Both cytotoxic ILCs and helper ILCs are included in the population of ILCs. ILC-specific progenitor cells that give a rise to ILC1s, ILC2s, and NCR+ ILC3s. immune checkpoint receptor that transmits inhibitory signals through the cytosolic ITIM and ITSM motifs upon recognition of its cognate ligands, PD-L1 and PD-L2. receptor of IL-33; strongly activates ILC2s and induces allergy. immune checkpoint receptor that transmits inhibitory signals through the cytosolic ITIM motif upon recognition of its cognate ligands, PVR and PVRL2. subtype of CD4+ helper T cells; produce type 1 cytokines, including IFNγ and TNFα. subtype of CD4+ helper T cells; produce type 2 cytokines, including IL-4, IL-5, and IL-13, and contribute to pathogenesis of allergy. antigen nonspecific innate immune response augmented by experience of activation.