ILC2: Powerful Regulators in Immunity and Allergic Responses

Innate lymphoid cells type 2 (ILC2s) are key regulators of immune responses, particularly in tissue homeostasis and reactions to infections or allergens. Unlike adaptive immune cells, ILC2s do not require antigen-specific receptors, allowing for rapid responses to environmental cues. Their cytokine production makes them essential in both protective immunity and conditions like asthma and allergic diseases. Understanding their function is crucial for developing targeted therapies for inflammatory disorders.

ILC2 Development And Differentiation

ILC2s originate in the fetal liver and bone marrow from common lymphoid progenitors (CLPs). Unlike adaptive immune cells, which require antigen receptor gene rearrangement, ILC2s follow a distinct lineage commitment process shaped by transcription factors.

A critical step in ILC2 development is the expression of the transcription factor GATA3, essential for their lineage specification. Studies show that deleting GATA3 in ILC precursors prevents mature ILC2 formation. Another key regulator, RORα, works with GATA3 to reinforce ILC2 identity, as seen in impaired ILC2 development in RORα-deficient models. These transcription factors, along with cytokine signaling, drive ILC2 maturation.

Cytokines like interleukin-7 (IL-7) and thymic stromal lymphopoietin (TSLP) are crucial for ILC2 differentiation, promoting survival and expansion. IL-7 maintains common innate lymphoid progenitors (CILPs), while TSLP enhances ILC2 commitment by activating STAT5, a transcription factor supporting proliferation. Mice lacking IL-7 receptor signaling show significant ILC2 reduction, highlighting the necessity of these cytokines.

The microenvironment also influences ILC2 differentiation. Retinoic acid signaling modulates ILC2 development in mucosal tissues, enhancing responsiveness to local cues. Lipid metabolism provides essential energy sources for expansion. These findings suggest ILC2 development is shaped by both genetic programming and external signals.

Distinct Phenotypic Markers

ILC2s are identified by a unique combination of surface markers and transcription factors. Unlike T or B cells, they lack antigen-specific receptors, requiring alternative characterization methods.

A defining feature of ILC2s is the interleukin-33 receptor (ST2), enabling responses to IL-33, a cytokine from epithelial and stromal cells. ST2-deficient mice exhibit reduced ILC2 numbers and impaired function, underscoring its importance.

ILC2s also express CD127, the alpha chain of the IL-7 receptor, essential for survival and development. While CD127 is found on other ILC subsets, co-expression with CD25 (IL-2 receptor alpha) refines identification. CD25 enhances ILC2 responsiveness to IL-2, supporting proliferation. Flow cytometry studies show CD25+ ILC2s expand more upon cytokine stimulation.

Intracellular transcription factors further define ILC2 identity. GATA3 is the master regulator, driving differentiation and function. Conditional deletion of GATA3 eliminates ILC2 populations, confirming its indispensable role. RORα supports ILC2 stability and is often used with GATA3 for identification.

Markers like KLRG1, associated with mature ILC2s in barrier tissues, provide insight into functional heterogeneity. KLRG1+ ILC2s exhibit heightened cytokine production compared to KLRG1- counterparts. ICOS and CRTH2 further refine ILC2 characterization, with CRTH2 being particularly useful for human ILC2 identification.

Tissue-Specific Roles

ILC2s reside in various tissues, adapting to each microenvironment. In the lungs, they populate the airway mucosa, responding dynamically to epithelial-derived signals. Their expansion and cytokine production maintain epithelial integrity and adapt to injury and repair needs.

In the skin, ILC2s localize in the dermis, influenced by lipid metabolism and neuroimmune interactions. Lipid mediators enhance their survival, while nerve fibers release neuropeptides that alter ILC2 behavior. This neuroimmune interaction is relevant in skin barrier disruptions, allowing rapid adaptation to external challenges.

The intestine presents a unique landscape where ILC2s integrate signals from the microbiota, diet, and epithelial cytokines. Bacterial metabolites modulate ILC2 activity, either enhancing or suppressing their function. Dietary vitamins, like vitamin A, shape ILC2 behavior, influencing responses to environmental shifts. This interplay highlights ILC2 adaptability in metabolically active tissues.

Cytokine Signaling Pathways

ILC2 function is regulated by cytokine signaling pathways dictating activation, survival, and expansion. Interleukin-33 (IL-33) signals through ST2, inducing ILC2 proliferation and cytokine secretion. Released by damaged epithelial cells, IL-33 sustains ILC2 activity via MyD88-dependent NF-κB and MAPK activation, driving effector gene expression.

Interleukin-25 (IL-25) enhances ILC2 activity through the IL-17RB receptor. Produced by tuft cells in mucosal tissues, IL-25 engagement amplifies type 2 cytokine production. IL-25 signaling induces a subset of highly proliferative inflammatory ILC2s (iILC2s), which are more responsive than homeostatic ILC2s. STAT5 activation further supports IL-25-mediated survival and function.

Interleukin-4 (IL-4) and interleukin-13 (IL-13) reinforce ILC2 activation, signaling through IL-4Rα and activating STAT6. IL-4 also influences ILC2 metabolism, shifting reliance to oxidative phosphorylation for sustained function in resource-limited conditions.

Cross-Talk With Other Immune Cells

ILC2s interact with other immune cells to coordinate responses. Their cytokines shape local immune environments, influencing dendritic cells (DCs), macrophages, T cells, and eosinophils.

ILC2-derived IL-13 enhances DC maturation and migration, improving naïve T cell priming. In turn, DCs regulate ILC2 activity by releasing IL-12 and type I interferons, limiting excessive activation. This bidirectional communication maintains immune balance.

Macrophages modulate ILC2 function by secreting amphiregulin, supporting tissue repair. ILC2-derived IL-5 recruits eosinophils, which release mediators that further shape ILC2 behavior. Regulatory T cells (Tregs) suppress ILC2 activity via TGF-β and IL-10, preventing excessive inflammation. These interactions highlight ILC2s as key immune regulators.

Contribution To Allergic Inflammation

ILC2s contribute to allergic diseases, driving airway hyperreactivity, skin inflammation, and gastrointestinal hypersensitivity. Their rapid IL-5 and IL-13 production in response to allergens makes them major players in allergic inflammation.

In asthma, ILC2s are hyperactivated by epithelial cytokines, leading to eosinophilic infiltration and mucus production. Elevated ILC2 numbers in bronchoalveolar lavage fluid correlate with disease severity. Blocking IL-33 signaling significantly reduces airway inflammation, underscoring their role in disease progression.

In atopic dermatitis, ILC2s accumulate in inflamed skin, exacerbating barrier dysfunction. Their interactions with sensory neurons contribute to itch responses, as neuropeptides like substance P enhance ILC2 activation. In food allergies, ILC2-driven inflammation disrupts intestinal barrier integrity, increasing allergen penetration. Depleting ILC2s in mouse models reduces intestinal inflammation and improves tolerance, suggesting potential therapeutic targets for allergic diseases.

ILC2 Responses To Microbial Exposure

Despite their association with type 2 immunity, ILC2s exhibit plasticity in response to microbial signals. Pathogen-associated molecular patterns (PAMPs) and microbial metabolites can enhance or suppress their function.

Helminth infections drive robust ILC2 activation, increasing IL-13 production for worm expulsion. Conversely, bacterial infections often trigger inhibitory pathways that limit ILC2 expansion. Exposure to microbial lipopolysaccharides (LPS) dampens ILC2 responses through Toll-like receptor signaling, demonstrating microbial influence on ILC2 activity.

Fungal infections, such as Candida albicans, induce IL-33 release, activating ILC2s and promoting tissue repair. However, excessive ILC2 activation can lead to fibrosis, requiring controlled regulation. Respiratory viruses like influenza suppress ILC2 responses via type I interferons, which may limit inflammation but also impair tissue repair. Understanding ILC2 integration of microbial signals provides insight into their broader role in immune defense and homeostasis.