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Review
. 2014 Apr:27:75-82.
doi: 10.1016/j.coi.2014.01.013. Epub 2014 Mar 3.

Regulation of the adaptive immune system by innate lymphoid cells

Matthew R Hepworth  1 , Gregory F Sonnenberg  2
Affiliations
Review

Regulation of the adaptive immune system by innate lymphoid cells

Matthew R Hepworth et al. Curr Opin Immunol. 2014 Apr.

Abstract

Innate lymphoid cells (ILCs) are a group of lymphocytes that promote rapid cytokine-dependent innate immunity, inflammation and tissue repair. In addition, a growing body of evidence suggests ILCs can influence adaptive immune cell responses. During fetal development a subset of ILCs orchestrate the generation and maturation of secondary lymphoid tissues. Following birth, ILCs continue to modulate adaptive immune cell responses indirectly through interactions with stromal cells in lymphoid tissues and epithelial cells at barrier surfaces. In this review we summarize the current understanding of how ILCs modulate the magnitude and quality of adaptive immune cell responses, and in particular focus on recent evidence suggesting that ILCs can also directly regulate CD4(+) T cells. Further, we discuss the implications that these pathways may have on human health and disease.

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Figures

Figure 1
Figure 1. RORγt+ ILCs orchestrate the formation of gut associated lymphoid tissue and the induction of IgA
RORγt+ ILCs orchestrate the formation of secondary lymphoid tissues in the intestine in response to commensal bacteria-derived signals. Lymphotoxin-mediated interactions with epithelial cells and stromal cells induce the production of chemokines, including CCL19, CCL20 CCL21 and CXCL13, which attract DCs, B cells and T cells to the intestine to form Peyer's patches and isolated lymphoid follicles (ILFs). This process is critical for the induction of IgA production by resident B cells. In addition M cells present in these lymphoid tissues sample antigen from the lumen and deliver to antigen-presenting cells in the underlying lymphoid tissue, possibly including MHCII+ ILCs.
Figure 2
Figure 2. RORγt+ ILCs regulate intestinal adaptive immune responses via IL-22
RORγt+ ILCs regulate epithelial barrier function and immune homeostasis in the intestine via the production of interleukin (IL)-22. ILC-derived IL-22 acts on epithelial cells and secretory cells to regulate epithelial barrier integrity and induce the production of antimicrobial peptides (AMPs) such as RegIIIγ and S100 family proteins, as well as mucins, which spatially segregate commensal bacteria from the epithelial barrier. ILC-derived IL-22-dependent pathways further regulate the growth of specific commensal bacteria species that are intimately associated with the host, such as segmented filamentous bacteria (SFB) and Alcaligenes/Achromobacter spp. Collectively, these responses limit the development of pathologic CD4+ T helper cell responses and intestinal inflammation.
Figure 3
Figure 3. Direct regulation of adaptive immunity by RORγt+ ILCs
Group 3 ILCs expressing the transcription factor RORγt directly interact with CD4+ T cells through receptor mediated cell-cell contact. ILCs regulate the magnitude and quality of the CD4+ T cell response via presentation of antigen in the context of MHC class II. In the steady state ILCs lack co-stimulatory molecule expression and appear to limit CD4+ T cell responses, however it remains to be tested whether ILCs can promote T cell proliferation under inflammatory settings. Furthermore, ILCs are located at distinct sites within the spleen and lymph nodes and act to critically regulate the survival of recirculating memory CD4+ T cells via interactions between ILC-expressed OX40L and CD30L and cognate receptors expressed by activated T cells. Finally, the ability of ILCs to regulate adaptive immune cell responses is not limited to T cells alone as ILCs may also produce cytokines and growth factors, including B cell-activating factor (BAFF), which support the function of B cells in lymphoid tissues.
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