What are ILC3 (Innate Lymphoid Cells 3) immune cells?

ILC3 Immune Cells: Critical Regulators of Mucosal Immunity

ILC3s (Innate Lymphoid Cells type 3) are innate immune cells defined by expression of the transcription factor RORγt that play crucial roles in mucosal barrier defense, lymphoid tissue development, and intestinal homeostasis.

Defining Characteristics of ILC3s

• Master transcription factor: RORγt (retinoic acid receptor-related orphan receptor γt) is the defining transcription factor for ILC3 development and function 1
• Origin: Develop from common lymphoid precursors but do not express antigen receptors like T and B cells 1
• Response pattern: Respond rapidly to environmental cues without requiring antigen specificity 2
• Key cytokines produced: IL-22 and IL-17A 2, 3

ILC3 Subsets and Heterogeneity

ILC3s can be divided into two major subsets based on surface marker expression:

1. NCR+ ILC3s:

   • Express the natural cytotoxicity receptor NKp46
   • Co-express transcription factor T-bet
   • Primarily produce IL-22 4, 3

2. NCR- ILC3s:

   • Include lymphoid tissue inducer (LTi) cells
   • Can be further identified by CCR6 expression
   • Produce both IL-17A and IL-22 2, 3

Developmental and Functional Roles

Embryonic Development

• LTi cells (a subset of NCR- ILC3s) are essential for the embryonic formation of peripheral lymph nodes and Peyer's patches 4
• Drive the genesis of gut lymphoid follicles through interactions with stromal cells 1

Intestinal Homeostasis

• Maintain mutualistic relationship with commensal microbiota 2
• Secrete IL-22 which:
  • Enhances epithelial barrier function
  • Induces antimicrobial peptide production
  • Promotes epithelial cell proliferation and survival 5
• Form part of a "glial-ILC3-epithelial cell unit" that senses environmental cues 6

Infection Defense

• Provide critical protection against attaching and effacing pathogens like Citrobacter rodentium 5
• Respond to bacterial products through pattern recognition receptors 1
• Mediate containment of colonizing bacteria through IL-22 production 1

Regulation and Signaling

• Neurotrophic factors: ILC3s express the RET receptor and respond to neurotrophic factors produced by glial cells 6
• Signaling pathways:
  • p38 MAPK/ERK-AKT cascade
  • STAT3 activation
  • These pathways control IL-22 production 6
• Microenvironmental sensing: Adjacent glial cells with stellate-shaped projections sense microenvironmental cues in a MYD88-dependent manner to control neurotrophic factors and innate IL-22 6

Clinical Relevance

• Inflammatory bowel disease: ILC3 dysfunction is implicated in susceptibility to bowel inflammation 6
• Mucosal infections: Critical for defense against intestinal pathogens 5
• Chronic rhinosinusitis: Increased in patients with type 2 inflammation and asthma 1
• Potential therapeutic target: Manipulation of ILC3 function could be relevant for treating inflammatory conditions 1

Research Considerations

When studying ILC3s, it's important to:

• Consider heterogeneity between subsets
• Account for tissue-specific localization and function
• Use appropriate markers (RORγt, CCR6, NKp46) for identification 2
• Recognize their plasticity and ability to adapt to environmental signals 3

ILC3s represent a fascinating bridge between innate and adaptive immunity, playing crucial roles in early life development of lymphoid tissues and continuing to orchestrate mucosal immune responses throughout life.