The immune system is a complex network of cells and organs working together to protect the body from disease. Within this intricate system, various cell types play distinct roles in maintaining health and responding to threats. Among these, innate lymphoid cells (ILCs) are a recently recognized family of immune cells.
ILC3s are a specific type of ILC, considered innate immune cells. They respond rapidly to signals without prior exposure to a specific pathogen, unlike adaptive immune cells such as T and B lymphocytes.
What Are ILC3s?
ILC3s, or Group 3 Innate Lymphoid Cells, are immune cells derived from common lymphoid progenitors, the same precursors that give rise to T and B lymphocytes. They do not possess antigen-specific receptors, responding promptly to signals from infected or damaged tissues.
These cells are predominantly found at mucosal surfaces, the body’s first line of defense against the external environment, including the gut, lungs, and skin. They are particularly abundant in the intestinal lamina propria and tonsils, but also present in the spleen, endometrium, decidua, and skin. Their development and function rely on specific internal regulators called transcription factors, notably RAR-related orphan receptor gamma t (RORγt). ILC3s can be broadly categorized into two subgroups: NCR+ ILC3 and NCR− ILC3, based on their expression of natural cytotoxicity receptors.
Key Functions of ILC3s in Health
ILC3s play a significant role in maintaining the body’s healthy state, particularly at mucosal surfaces. They help preserve the integrity of these barriers, responding to environmental cues and promoting tissue health. This involves encouraging the repair of epithelial cells, which form the lining of these surfaces, and stimulating the production of mucus, a protective layer that traps pathogens and prevents their entry.
ILC3 function also involves interaction with the commensal microbiota, the beneficial bacteria residing in the gut. ILC3s contribute to shaping and responding to this microbial environment, fostering a balanced relationship that supports overall health. They maintain immune tolerance towards these beneficial gut bacteria, preventing excessive immune responses that could lead to inflammation.
ILC3s primarily exert their beneficial effects by producing specific signaling molecules called cytokines. The most prominent of these are Interleukin-17 (IL-17) and Interleukin-22 (IL-22). IL-22 is important for promoting epithelial cell proliferation and the production of antimicrobial molecules, which directly combat pathogens. IL-17 helps recruit immune cells like neutrophils and enhances host defense against extracellular bacteria and fungi.
ILC3s in Disease
Despite their beneficial roles in maintaining health, ILC3s can contribute to disease when their activity becomes dysregulated. In inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, ILC3s can drive chronic inflammation. This often occurs through the excessive production of pro-inflammatory cytokines like IL-17 and IL-22, which exacerbate mucosal damage. A reduction in ILC3 frequency in inflammatory gut tissue is also linked to disease severity.
ILC3s are also implicated in skin inflammatory conditions like psoriasis, where their dysregulation can lead to uncontrolled inflammation. In respiratory conditions, ILC3s contribute to asthma and allergic airway inflammation.
In the context of cancer, ILC3s exhibit a complex, dual role. While they can sometimes inhibit tumor growth, they are more often associated with promoting tumorigenesis, especially in intestinal cancers. They can drive tumor development through inflammatory factors like IL-17 and IL-22, and their dysfunction can lead to dysregulation of other immune cells, promoting tumor progression. ILC3s can also differentiate into regulatory ILCs and secrete IL-10, which can promote tumor growth.
Regulation and Therapeutic Potential
The activity of ILC3s is influenced by a variety of environmental factors. These include cytokines released by other immune cells, signals from the gut microbiota, and dietary components. For instance, certain microbial metabolites and dietary vitamins, such as vitamin D, can modulate ILC3 function and their ability to produce cytokines like IL-22.
Understanding these regulatory mechanisms opens avenues for therapeutic interventions. Modulating ILC3 activity is an emerging approach for treating diseases where these cells play a significant role. Strategies could involve blocking the pro-inflammatory cytokines produced by dysregulated ILC3s, such as IL-17A or IL-22, to reduce inflammation. Alternatively, therapeutic approaches might focus on manipulating ILC3 activity to restore immune balance, potentially by influencing their differentiation or promoting their beneficial functions.