The review’s central thesis is that mature ILC identity is not fixed at birth. Developmental programming establishes each cell’s lineage potential through an interconnected network of transcription factors, including NFIL3, TOX, TCF-1, GATA3, and the inhibitor Id2, which suppresses alternative B- and T-cell fates while supporting innate lymphoid commitment. Intermediate progenitors such as the common helper innate lymphoid progenitor, described by Klose and colleagues, generate helper-like ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer cells while excluding conventional lymphocyte potential. For the type 2 compartment most relevant to allergy, murine genetic studies identify Bcl11b as essential for ILC2 development, and human experiments confirm that GATA3 is required for cytokine production by these cells.

Recent findings have complicated the traditional fetal-liver-to-bone-marrow developmental sequence. In the human embryo, Ni and colleagues identified yolk-sac-derived lymphoid-biased progenitors that appear before definitive hematopoietic stem cells, preferentially generating ILCs and dendritic cells. In mice, Wang and colleagues showed that fetal-liver-derived ILC progenitors seed developing organs, where local niches direct differentiation into tissue-associated precursors that can persist into adulthood and maintain local ILC pools independently of continuous bone-marrow output. The result is a layered model of ILC ontogeny in which embryonic, fetal, and adult sources contribute differently depending on developmental stage, tissue, and inflammatory context.

Once ILCs colonize barrier tissues, environmental education takes over. Parabiosis experiments demonstrated that ILCs in the lung, intestine, adipose tissue, and skin persist mainly through local self-renewal rather than continuous replacement from the circulation, allowing them to integrate information about epithelial integrity, stromal activity, vascular function, neuronal signaling, and microbial composition before mounting responses. Single-cell transcriptomics has reinforced this picture of tissue conditioning: ILC2s isolated from different organs retain a conserved lineage program while acquiring distinct tissue-specific signatures, and human datasets across blood, lymphoid tissue, mucosa, and tumors show both conserved features and strong tissue-specific imprinting. Spatial mapping by Van Acker and colleagues further revealed that ILC subsets occupy non-random positions within human lymphoid tissues, preferentially adjacent to functionally corresponding T-cell populations.

Perhaps the most striking dimension of ILC biology is plasticity. Human ILC2s exposed to IL-12 and IL-1β upregulate T-bet, gain responsiveness to IL-18, and produce interferon-γ while reducing canonical type 2 functions, effectively acquiring ILC1-like characteristics; IL-4 can reverse this shift in culture. Comparable flexibility exists within the ILC3 compartment, where inflammatory mediators promote ILC1-like conversion, while stabilizers such as the circadian nuclear receptors REV-ERBα and REV-ERBβ preserve intestinal ILC3 identity. The authors caution, however, that cytokine-driven conversion in culture demonstrates potential rather than clinical reality: claims of durable lineage conversion in human allergic tissue require longitudinal and perturbational evidence, not merely shifts in surface markers.

Under physiological conditions, ILCs perform remarkable housekeeping duties. ILC3s serve as central regulators of intestinal epithelial defense through IL-22, which can act directly on intestinal stem cells to support epithelial regeneration after injury. In the respiratory tract, lung-resident ILC2s accelerate recovery from influenza-induced epithelial damage through amphiregulin production, which signals via the epidermal growth factor receptor to support epithelial and stromal-cell survival and proliferation. In adipose tissue, ILC2-derived IL-5 and IL-13 sustain eosinophils and alternatively activated macrophages, contributing to an anti-inflammatory environment and even linking tissue immunity to thermogenesis and energy expenditure. The outcome of these pathways depends critically on magnitude, timing, and duration: transient mediator production supports repair, whereas persistent production drives goblet-cell metaplasia, fibroblast activation, extracellular matrix deposition, and remodeling.

ILCs also operate within multicellular niches that increasingly appear central to both health and disease. Fibroblasts, once viewed as passive matrix producers, actively organize ILC compartments: in the intestine, distinct fibroblastic reticular-cell populations support different ILC pools, and in experimental arthritis, Rauber and colleagues identified CD200-positive fibroblasts that interact with ILC2s to promote a pro-resolving tissue environment. Conversely, in experimental silicosis, mechanically activated fibroblasts redirect ILC phenotype through Notch3- and IL-18-dependent signaling, illustrating how stromal instruction can push ILCs toward pathology. Neuronal circuits add another layer: the neuropeptide neuromedin U, released by enteric and sensory neurons, potently activates ILC2s through its receptor, while sympathetic β2-adrenergic signaling restrains excessive type 2 responses, and vasoactive intestinal peptide links feeding behavior to intestinal ILC3 function.

The review’s most clinically consequential section addresses what happens when these homeostatic programs fail. In asthma, epithelial-derived IL-33, IL-25, and TSLP activate airway ILC2s, which produce IL-5 and IL-13 to drive eosinophilic inflammation and airway hyperresponsiveness. Christianson and colleagues showed that established allergic airway disease is maintained through interacting feedback circuits involving IL-33, ILC2s, and adaptive lymphocytes, while Verma and colleagues demonstrated that experimental asthma persists even in mice lacking the IL-33 receptor because TSLP-driven IL-9-positive and IL-13-positive ILC2 subpopulations emerge to sustain inflammation. This functional redundancy helps explain why blockade of single epithelial alarmins sometimes yields limited efficacy. Human studies confirm activated ILC2 accumulation in bronchoalveolar lavage fluid, sputum, and biopsies of eosinophilic asthma patients, with the greatest expansion in severe disease.

One of the most clinically significant findings involves corticosteroid resistance, a defining feature of severe asthma. Kabata and colleagues demonstrated that TSLP protects human ILC2s from glucocorticoid-mediated suppression through STAT5 signaling, and Liu and colleagues showed that in airway ILC2s from severe asthma patients, TSLP activates MEK and STAT5 pathways that restore cytokine production despite dexamethasone treatment; pharmacological inhibition of these pathways largely recovered steroid sensitivity. Subsequent work revealed that combined IL-33, TSLP, and IL-7 signaling activates JAK-STAT5-dependent expression of the anti-apoptotic molecule Bcl-xL alongside PI3K-Akt-mTOR pathways, keeping activated ILC2s alive during chronic inflammation. The reviewers also highlight newer regulators, including NFκB1, which restrains memory-like ILC2 responses, and the chromobox protein CBX7, whose genetic deletion or pharmacological inhibition markedly reduced cytokine production and suppressed allergic airway inflammation in multiple models.

Similar failed-homeostasis logic extends across allergic organs, though the authors are careful to note that each disease follows its own tissue-specific architecture. In chronic rhinosinusitis with nasal polyps, IL-33-responsive cells in nasal polyps produce IL-13, and ILC2s are enriched and activated in polyp tissue, although cross-sectional findings cannot establish causality. In eosinophilic esophagitis, Doherty and colleagues found expanded ILC2 populations correlating with tissue eosinophilia and disease activity, while recent single-cell atlases of active and remitting disease reveal dynamic rewiring across epithelial, stromal, myeloid, and lymphoid compartments. In atopic dermatitis, expanded cutaneous ILC2s respond to epithelial cytokines, and sensory neurons co-opt IL-4 and IL-13 signaling through neuronal IL-4Rα and Janus kinase pathways to mediate chronic itch, creating a self-reinforcing scratch-barrier injury cycle. Approved biologics targeting TSLP, IL-4Rα, IL-5, IL-13, and IgE demonstrate clinical benefit across these diseases, but because these pathways are shared by multiple cell types, clinical responses do not establish ILC2-specific efficacy. The reviewers argue that the next therapeutic frontier lies not in simply suppressing inflammation but in restoring tissue homeostasis itself, requiring longitudinal human studies, perturbable ex vivo systems, and matched animal models to identify which niche signals permit successful resolution and which stabilize the fibroblast activation and matrix deposition that make allergic disease chronic.

Subject of Research: Innate lymphoid cells as regulators of tissue homeostasis and their role in chronic allergic diseases

Article Title: Innate lymphoid cells as central regulators of tissue homeostasis: implications for allergic diseases

Article References: Sirohi, K., & Yadav, S. (2026). Innate lymphoid cells as central regulators of tissue homeostasis: implications for allergic diseases. Frontiers in Allergy, 7, Article 1954214. https://doi.org/10.3389/falgy.2026.1954214

Image Credits: AI Generated

DOI: 10.3389/falgy.2026.1954214

Keywords: innate lymphoid cells, ILC2, tissue homeostasis, allergic disease, asthma, atopic dermatitis, eosinophilic esophagitis, chronic rhinosinusitis, epithelial alarmins, IL-33, TSLP, neuroimmune signaling