Dichotomous Regulation of Acquired Immunity by Innate Lymphoid Cells

Abstract

The concept of innate lymphoid cells (ILCs) includes both conventional natural killer (NK) cells and helper ILCs, which resemble CD8⁺ killer T cells and CD4⁺ helper T cells in acquired immunity, respectively. Conventional NK cells are migratory cytotoxic cells that find tumor cells or cells infected with microbes. Helper ILCs are localized at peripheral tissue and are responsible for innate helper-cytokine production. Helper ILCs are classified into three subpopulations: T_H1-like ILC1s, T_H2-like ILC2s, and T_H17/T_H22-like ILC3s. Because of the functional similarities between ILCs and T cells, ILCs can serve as an innate component that augments each corresponding type of acquired immunity. However, the physiological functions of ILCs are more plastic and complicated than expected and are affected by environmental cues and types of inflammation. Here, we review recent advances in understanding the interaction between ILCs and acquired immunity, including T- and B-cell responses at various conditions. Immune suppressive activities by ILCs in particular are discussed in comparison to their immune stimulatory effects to gain precise knowledge of ILC biology and the physiological relevance of ILCs in human diseases.

Keywords: IL-10; ILC1; ILC2; ILC3; NK cells; exhausted-like ILC2; innate lymphoid cells.

Figure 1

Similarities between innate lymphoid cells (ILCs) and T cells. TF: transcription factor.

Figure 2

Natural-killer (NK) cells and ILC1s positively or negatively regulate acquired immunity. (a) NK cells enhance Type I immunity mediated by T_H1 cells. NK cells are highly activated after mutual interaction with dendritic cells (DCs) that sense pathogen-associated pattern molecules (PAMPs) such as virus-derived RNAs and DNAs. Activated NK cells secrete IFN-γ for T_H1 skewing. (b) NK cells and ILC1s suppress antivirus acquired immunity. NK cells attack CD4⁺ T cells, CD8⁺ T cells, and infected-DCs to inhibit acquired immune responses against virus infection. PDL-1 on hepatic ILC1s suppresses anti-virus CD4⁺ and CD8⁺ T cells through PD-1 on T cells. IL-10-producing NK cells and dysfunctional NK cells may be involved in suppressing cytotoxic T lymphocyte (CTL) responses.

Figure 3

ILC2s modulate acquired immune responses. (a) ILC2s enhance Type II immune responses against parasitic worms. ILC2s secrete IL-5 that promotes B1-cell proliferation. OX40L/OX40 signaling is required for B2-cell proliferation and IgE production against helminth. ILC2s elicit T_H2 polarization through recruitment of CCL17-producing DCs, induction of M2 macrophages, and direct antigen presentation. OX40L on ILC2s contributes to T_H2 proliferation by interacting with OX40 expressed on T_H2 cells. (b) Immunosuppressive function of ILC2s. IL-9 stimulates ILC2 survival and activity by autocrine and support Treg-cell expansion via GITRL/GITR, ICOSL/ICOS, and OX40L/OX40 signaling. At the site of severe or chronic allergic inflammation, ILC2s can be dysfunctional “exhausted-like” ILC2s that express checkpoint inhibitory receptors and produce immunosuppressive IL-10. Induction of exhausted-like phenomenon in ILC2s suppresses allergy pathogenesis associated with eosinophil recruitment and T_H2 induction.

Figure 4

ILC3s control subsequent acquired immunity. (a) ILC3s augment T_H1 and T_H17 differentiation. Colonization of segment filamentous bacteria (SFB) enhances T_H17 differentiation through ILC3-derived IL-22 that induces intestinal epithelial cells to secrete serum amyloid A (SAA) for T_H17 differentiation. ILC3s present antigens to naïve CD4⁺ T cells and elicit T_H1 differentiation in colitis. NCR⁺ ILC3s acquire an ability to produce IFN-γ in an IL-12-dependent manner. ILC3s produce lymphotoxins (LTs) that support T-cell-dependent and -independent IgA production in the intestine. At secondary lymphoid organs (SLOs), ILC3s activate marginal zone B cells (MZ-B) by direct contact. (b) Immunosuppressive roles of ILC3s in regulating acquired immunity. ILC3s promote Treg expansion by IL-2 and OX40/OX40L signaling. ILC3s suppress differentiation of microbiota-specific T_H1 and T_H17 cells by antigen presentation without costimulatory signals. Similarly, Tfh-cell differentiation in colon mesenteric lymph nodes is suppressed by ILC3s. LP: lamina propria.