Innate Lymphoid Cell Biology and Immune Function

Innate lymphoid cells (ILCs) constitute a family of lymphocytes that mirror adaptive T-cell functions yet respond rapidly to environmental cues without antigen-specific receptors. They are broadly divided into three groups: ILC1, ILC2 and ILC3. Group 1 ILCs, including natural killer cells and ILC1, produce interferon-γ and mediate early defence against intracellular pathogens. ILC2 secrete type 2 cytokines such as interleukin-5 and interleukin-13, promoting responses to helminths and tissue repair. Group 3 ILCs (ILC3), characterised by the transcription factor RORγt, deliver interleukin-17 and interleukin-22 to maintain mucosal barriers and orchestrate interactions with the microbiota. A further subset, lymphoid tissue inducer cells, shapes lymphoid organogenesis. Within tissues, ILC subsets adapt to local microenvironments through dynamic transcriptional programmes, guided by signals such as Wnt/β-catenin and transforming growth factor-β. ILC plasticity underpins functional shifts that contribute to homeostasis, inflammation and tissue regeneration. Aberrant ILC activity has been linked to inflammatory bowel disease, asthma, viral infections and cancer, making these cells targets for novel immunotherapies and tissue-protective strategies.

Research from Nature Portfolio

Recent studies have uncovered how dysregulated Wnt/β-catenin signalling in group 3 ILCs disrupts intestinal homeostasis. Elevated β-catenin in ILC3s was shown to repress RORγt expression by altering chromatin accessibility and inhibiting the JunB transcriptional programme, leading to impaired ILC3 proliferation, barrier dysfunction and inflammation that promotes tumour development. This work highlights a critical Wnt–TCF-1–JunB axis in ILC3 biology and suggests that modulation of β-catenin activity could restore mucosal integrity in inflammatory and neoplastic settings.

Foundational research has also illuminated migratory behaviours of RORγ+ ILC3s. Through photoconversion of intestinal cells, ILC3s were observed to traffic constitutively from the gut to mesenteric lymph nodes via a CCR7-dependent mechanism. Within these draining nodes, ILC3s occupy interfollicular niches and present microbial antigens, shaping T-cell responses. This work reveals that tissue-to-lymph-node migration is a key parameter in ILC3-mediated coordination of mucosal immunity.

Innate Lymphoid Cell Biology and Immune Function publication trend

The graph below shows the total number of articles in innate lymphoid cell biology and immune function across all publications each year (not limited to Nature Index journals).

Technical terms

Innate lymphoid cell (ILC): A lymphocyte lacking antigen receptors that responds rapidly to cytokines and microbial signals to regulate immunity and tissue homeostasis.

ILC3: Group 3 innate lymphoid cells defined by RORγt expression and production of interleukin-17 and interleukin-22, important for mucosal defence and lymphoid tissue formation.

RORγt: A lineage-defining transcription factor that drives development and function of group 3 ILCs and Th17 cells.

Wnt/β-catenin signalling: A pathway in which Wnt ligands stabilise β-catenin, allowing it to translocate to the nucleus and regulate gene expression.

CCR7: A chemokine receptor that guides immune cell migration to lymph nodes in response to its ligands CCL19 and CCL21.

Oxysterol: An oxidised cholesterol derivative that acts as a chemoattractant or signalling molecule in immune and metabolic pathways.

GPR183: A G-protein-coupled receptor for oxysterols that regulates immune cell positioning and lymphoid tissue development.

References

1. Tissue-specific features of innate lymphoid cells in antiviral defense. Cellular & Molecular Immunology (2024).
2. Dysregulation of Wnt/β-catenin signaling contributes to intestinal inflammation through regulation of group 3 innate lymphoid cells. Nature Communications (2024).
3. CCR7-dependent trafficking of RORγ+ ILCs creates a unique microenvironment within mucosal draining lymph nodes. Nature Communications (2015).
4. Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation. Immunity (2018).