Functional interactions between innate lymphoid cells and adaptive immunity - PubMed (original) (raw)

Review

Functional interactions between innate lymphoid cells and adaptive immunity

Gregory F Sonnenberg et al. Nat Rev Immunol. 2019 Oct.

Abstract

Innate lymphoid cells (ILCs) are enriched at barrier surfaces of the mammalian body where they rapidly respond to host, microbial or environmental stimuli to promote immunity or tissue homeostasis. Furthermore, ILCs are dysregulated in multiple human diseases. Over the past decade, substantial advances have been made in identifying the heterogeneity and functional diversity of ILCs, which have revealed striking similarities to T cell subsets. However, emerging evidence indicates that ILCs also have a complex role in directly influencing the adaptive immune response in the context of development, homeostasis, infection or inflammation. In turn, adaptive immunity reciprocally regulates ILCs, which indicates that these interactions are a crucial determinant of immune responses within tissues. Here, we summarize our current understanding of functional interactions between ILCs and the adaptive immune system, discuss limitations and future areas of investigation, and consider the potential for these interactions to be therapeutically harnessed to benefit human health.

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Figures

Figure 1 ∣. A dialogue between innate and adaptive lymphocytes throughout a lifetime.

LTi cells promote secondary lymphoid organogenesis prior to birth, and along with ILC2, seed multiple lymphoid or barrier tissues during fetal development and neonatal periods. Following birth, ILC2 expand within tissues and T-bet+ ILC3s expand in the intestine as a result of colonization with microbiota and exposure to other environmental stimuli. It is during this period and throughout stages of homeostasis that ILCs interact with adaptive immunity to promote tissue homeostasis. This occurs primarily through bi-directional interactions, and includes direct or indirect modulation of multiple facets of innate and adaptive immunity. Conversely, in the context of aging, infection, inflammation or immunodeficiency, ILCs and adaptive immunity engage in a pro-inflammatory Interaction that is a crucial determinant of the immune response.

Figure 2 ∣. Anatomical distribution of ILCs and their interface with adaptive immunity.

The ability of ILCs to interact with adaptive immune cells and modulate their responses is highly dependent upon co-localization of ILCs within tissues and lymphoid structures. This is best characterized for ILC2s (red) and ILC3s (green), which are constitutively found within both mucosal barrier tissues and associated lymphoid tissues. Within the intestinal tissue, ILCs are largely found either localized within lymphoid structures such as the Peyer’s patches or cryptopatches of the small intestine or within the lamina propria. Localization of LTi-like ILC3s to cryptopatches is controlled through sensing of stromal derived cues via receptors such as GPR183, whereas T-bet+ ILC3s localization within the intestinal lamina propria is mediated via CXCR6-dependent homing. Increasing evidence suggests that subsets of ILCs (specifically, inflammatory ILC2s) can migrate out of tissues via blood vessels in an S1P-dependent manner in the context of infection and inflammation and establish residence in peripheral organs, including the lungs. Within such peripheral tissues, ILC2s are further found localized within “adventitial cuffs”, tissue niches formed around airways and blood vessels that are further characterized by stromal populations expressing ILC2-activating cytokines in multiple tissues. Additionally, ILCs can migrate in the lymphatics to draining lymph nodes, such as the intestinal-associated mesenteric lymph node (MLN) chain, in a CCR7-dependent manner and co-localize at the inter-follicular border between the B cell follicle and T-cell zone. ILCs interact with many types of T cells, inlcuding TFH cells, Treg cells, TH1 cells, TH2 cells and TH17 cells, which is described in greater detail in Figures 3-5.

Figure 3 ∣. ILCs modulate adaptive immunity by producing soluble mediators with direct or indirect effects.

ILCs modulate adaptive immune responses through the production of soluble effector molecules that exert their effects either directly or through the activation of bystander cells such as epithelial cells and myeloid cells (dendritic cells (DCs) and mononuclear phagocytes (MNPs)) in the tissue. a) ILC2s are predominantly activated within tissues following production of cytokines, including IL-25, IL-33 and TSLP. Subsequently, ILC2 provide direct help for B cells within the tissue through production of IL-5 and IL-6. Conversely, IL-13 produced by ILC2s induces DC migration to the draining lymph node and production of the chemokine CCL17, which subsequently functions to rapidly recruit memory TH2 cells to the airways in the context of airway inflammation or infection. b) NK cells and ILC1 may also have roles in modulating T cells responses, in particular Th1 responses, through production of IFN-γ. This may occur directly or indirectly via myeloid cell populations. c) Similarly, ILC3s in the intestinal tract and lymphoid tissues produce lymphotoxin to support B cell class switching and IgA production. ILC3 in the spleen express the B cell-survival factors (BAFF/APRIL), but this has not yet been reported at mucosal sites. Additionally, multiple reports implicate a complex communication between ILC3s, MNPs and Treg cells in the intestine, which together reinforces tolerance and tissue homostasis. This is achieved either directly through ILC3-derived IL-2 secretion, which provides crucial survival signals to Treg cells, or indirectly via GM-CSF. The latter pathway subsequently results in a feedback loop whereby MNPs respond by producing IL-10 and RA to further reinforce Treg cell conversion and maintenance. ILC3 production of IL-22 has also been linked to induction of intestinal epithelial cell-derived SAA, which supports Th17 cell responses. Th17 cell production of IL-17A induces antimicrobial responses from intestinal epithelial cells and controls the composition of the microbiota, including limiting colonization with segmented filamentous bacteria (SFB).

Figure 4 ∣. ILCs control adaptive immunity through direct cellular interactions.

ILC subsets, in particular ILC2s and ILC3s, express a range of surface molecules that facilitate direct cell–cell interactions and modulation of T cell responses in health and disease. a) ILC3s constitutively express MHC class II molecules in intestinal-draining lymphoid tissues and the colon at homeostasis. In this context, ILC3s lack surface co-stimulatory molecules and present antigens to microbiota-specific CD4+ T cells, resulting in the induction of cell death. Similarly, interactions with TFH cells within the mesenteric lymph node limits TFH cell-derived IL-4 and subsequent class-switching of mucosal B cells to produce IgA. ILC3 also express PD-L1, which may interact with PD-1 on TFH cells, but this has yet to be extensively explored. ILC3 expression of non-canonical co-stimulatory molecules such as OX40L and CD30L can support memory T cell responses, although it is unknown whether this also requires MHC class II-dependent antigen presentation. b) By contrast, in the context of a maladapted immune system, such as in lymphopenia or chronic inflammation, the antigen-presenting function of ILC3s can change markedly. In response to pro-inflammatory cytokines such as IL-1β and TL1A, ILC3s upregulate expression of co-stimulatory molecules including CD80, CD86 and OX40L and promote inflammatory T cell effector responses. c) Upon activation by IL-25 and/or IL-33 (derived from epithelial cells, stromal cells and myeloid cells), ILC2s upregulate expression of MHC class II and co-stimulatory molecules such as CD80 and CD86, which facilitate direct interactions with naïve T cells and promote priming of TH2 cells in the context of allergic airway inflammation or infection. In addition, ILC2 expression of OX40L promotes the proliferation and effector responses of TH2 cells and further supports expansion of OX40+ Treg cells. ILC2s further enhance Treg cell responses through provision of surface ICOS, which binds ICOSL expressed on Treg cells.

Figure 5 ∣. Counter regulation of ILCs by adaptive immunity.

Adaptive immunity can promote or inhibit ILC responses through a number of distinct mechanisms. a) ILC3 and ILC1 responses can be limited by Tregs through the direct sequestration of IL-2 or indirect regulation of MNP-derived IL-23. Furthermore, ILC3 responses are suppressed through the competition with adaptive immunity for pro-survival cytokines or by adaptive immune control of the microbiota. Conversely, ILC3 responses are promoted following antigen-dependent encounters with NKT cells, and the population of size of ILC3 is supported through undefined mechanisms by T and B cells in secondary lymphoid tissues. b) ILC2 responses are suppressed by Treg cell-derived IL-10 and TGF-β or TH1 cell-derived IFNγ, while ILC2 responses are conversely enhanced by TH2 cell-derived IL-2 in a context-dependent manner.

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Functional interactions between innate lymphoid cells and adaptive immunity - PubMed (original) (raw)