Innate lymphoid cells: parallel checkpoints and coordinate interactions with T cells
Introduction
Host immunity is composed of both the innate immune system and the adaptive immune system that form layered networks to defend the body against infection and maintain normal tissue homeostasis. Innate lymphoid cells (ILCs) are an expanding family of lymphocytes that lack somatically rearranged antigen specific receptors, produce significant amounts of cytokines and can be cytotoxic following activation. The distinct cytokines produced by each ILC subset are akin to the signature cytokines found for different CD4+ T helper cell (Th) subsets responding to their cognate antigens (Figure 1). Thus two apparently analogous systems have emerged allowing early responses initiated by ILCs to be coupled to T cell responses that ensure robust immunity and maintenance of host integrity.
Early work on ILCs has revealed striking similarities between the various subsets of ILCs and T cells [1] (Figure 1). These features include the shared expression of T-bet and IFN-γ by ILC1 and Th1 cells, GATA-3, IL-5 and IL-13 by ILC2 and Th2 cells, RORγt, IL-17 and IL-22 by ILC3 and Th17/Th22 cells as well as Eomes, IFN-γ and cytolytic molecules by CD8+ T cells and NK cells. Therefore, it has been tempting to speculate that ILCs could be considered as potential innate counterparts of T cells. The recent availability of ILC subset transcriptomic profiles [2•] allowed us to further test this possibility by comparing them to the transcriptomic profiles of T cell subsets using principal component analysis. Based on the expression of 14 261 genes, the first component separates T cells from ILC (19% overall variability of the data set), showing that T cell subsets are more related to each other than they are to ILC subsets (Figure 2). The second component tends to separate natural killer (NK) cells, ILC1 and CD8+ T cells to ILC2, ILC3 and Th cells (14% overall variability of the data set). Contrary to the prevailing view, ILC1 are not related to Th1 but clearly defined as the opposite of Th1 cells on the first two components. This analysis illustrates the limits of the assimilation of ILCs to innate counterparts of T cells. Indeed, the relationships between ILCs and T cells appear numerous and complex. They include similarities, differences, cooperation and redundancy that will be reviewed here.
Section snippets
IL-15 is a common key factor for NK cells, ILC1 and CD8+ T cells
Cytotoxic lymphocytes are generally viewed as immune cells that can directly puncture the outer membrane of target cells (via Perforin) to deliver a toxic load of proteases (Granzyme B) resulting in apoptosis [3]. Transcriptomic profiles revealed that NK cells, ILC1 and CD8+ T cells all fit this description and express high levels of transcripts encoding these enzymes, as well as IFN-γ, whose production is another cardinal feature of cytotoxic cells.
IL-15 is a pleiotropic cytokine derived from
Articulation of the functions of ILC2s and Th2s
Group 2 ILC have been shown to be present at multiple sites including the spleen, liver, lung, intestinal lamina propria, skin, bone and adipose tissue. They have been shown to have an important role in early innate responses to helminth infections, in a variety of allergic inflammatory responses and in the maintenance of metabolic homeostasis. ILC2 are defined by their expression of the IL-33 receptor (IL-33R, or ST2) and transcriptional regulators Id2, Rorα, GATA3 and Bcl11b [31•, 32•, 33•, 34
Redundancy and complementarity of ILC3 and T cells
ILC3 are mainly associated with mucosal tissues where they can exert various functions. In the gut, ILC3 can be divided into two main subsets based on the cell surface expression of the natural cytotoxicity receptor (NCR) NKp46 (also referred as to NCR1 or CD335) in humans and mice [2•, 49]. However, ILC3 are more heterogenous as NCR−ILC3 include lymphoid-tissue inducer-like cells that express CCR6 and neuropilin 1 (Nrp1), and other NCR−ILC3 that can generate NCR+ILC3 via T-bet- and
Concluding remarks
The articulation between T and ILCs suggest that ILCs may contribute non-redundant functions when T cells are absent or not fully functional, prompting to dissect the role of ILCs during gestation, in newborns, in elderly as well as in conditions of immune-deficiency such as during viral infections or transplantation. In addition, there are a number of questions that remain to be addressed to fully appreciate the links between ILCs and T cells, such as:
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what is the differential sensitivity of
Conflict of interests
E.V. is the cofounder and a shareholder of Innate Pharma. The other authors have no conflicting financial interest to declare.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgments
G.T.B. and N.H. laboratories are supported by grants and fellowships from the National Health and Medical Research Council (NHMRC) of Australia (G.T.B., N.H.) and the Australian Research Council (G.T.B.), the Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC IRIIS. The EV laboratory is supported by the European Research Council (THINK Advanced Grant), the Ligue Nationale contre le Cancer (Equipe Labellisée) and by institutional grants from INSERM,
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