Innate Lymphoid Cells and Intestinal Inflammatory Disorders

Abstract

Innate lymphoid cells (ILCs) are a population of lymphoid cells that do not express T cell or B cell antigen-specific receptors. They are largely tissue-resident and enriched at mucosal sites to play a protective role against pathogens. ILCs mimic the functions of CD4 T helper (Th) subsets. Type 1 innate lymphoid cells (ILC1s) are defined by the expression of signature cytokine IFN-γ and the master transcription factor T-bet, involving in the type 1 immune response; ILC2s are characterized by the expression of signature cytokine IL-5/IL-13 and the master transcription factor GATA3, participating in the type 2 immune response; ILC3s are RORγt-expressing cells and are capable of producing IL-22 and IL-17 to maintain intestinal homeostasis. The discovery and investigation of ILCs over the past decades extends our knowledge beyond classical adaptive and innate immunology. In this review, we will focus on the roles of ILCs in intestinal inflammation and related disorders.

Keywords: ILC1; ILC2; ILC3; intestinal inflammation.

Figure 1

ILC development. There are several similarities between the development of innate lymphoid cells (ILCs) and T cells. Both T cells and ILCs are derived from common lymphoid progenitors (CLPs). T cells go through the CD4/CD8 double-negative (DN) and double-positive (DP) stages and then differentiate into CD4 or CD8 single positive (SP) cells. CD4 SP cells can further differentiate into Th1, Th2, Th17, or Tregs in certain environments. All ILCs are generated from common helper-like innate lymphoid progenitors (ChILPs). While the non-LTi ILCs are generated from PLZF-expressing common progenitors (ILCPs), LTi cells develop from a distinct progenitor which has no history of PLZF expression but depends on the transcription factor RORγt for their development. As during T helper (Th) cell differentiation, ILCPs can give rise to ILC1, ILC2, and ILC3 subtypes, whose development depends on the master transcription factors T-bet, GATA3, and RORγt, respectively. ETP, early thymic progenitors. Background color: blue: T cell lineage; green: ILC lineage.

Figure 2

ILC function. At the maturation stage, CD4⁺ Th cells and ILC subsets produce similar effector cytokines and share same master transcription factors for their functions. Th1 cells and ILC1s are capable of producing IFN-γ and are important for the clearance of viruses, intracellular bacteria, or protozoa and mediate autoimmunity. Th2 cells and ILC2s, by producing IL-5 and IL-13, are important for helminth expulsion and are involved in allergy. Th17 cells and ILC3s, through secreting IL-17 and IL-22, are critical for protective immune responses against fungal and extracellular bacterial infections and contribute to autoimmunity.

Figure 3

ILCs in intestine. In the healthy intestine, ILCs maintain intestinal homeostasis through induction of protective immune responses against pathogenic microbes and keep the intestinal barrier integrity. In response to microbial stimuli, dendritic cells (DCs) and macrophages may stimulate ILC1 responses to intracellular pathogens through secreting IL-12 and IL-18, and they induce ILC3 responses against extracellular bacteria and fungi through secreting IL-23 and IL-1β. On the other hand, epithelial-derived factors, such as IL-33 and IL-25, may induce type 2 cytokine secretion by ILC2s and in turn contribute to the expulsion of helminths.