Innate lymphoid cells: parallel checkpoints and coordinate interactions with T cells

doi:10.1016/j.coi.2015.11.008

Current Opinion in Immunology

Volume 38, February 2016, Pages 86-93

https://doi.org/10.1016/j.coi.2015.11.008 Get rights and content

Highlights

•
The phenotypic and functional parallels between ILC and T cell subsets establish common immune checkpoints.
•
Complementarity and redundancy between ILCs and T cells ensures immune protection.
•
The immune function of ILCs are revealed in conditions of deficiencies of adaptive immunity.

Protection of epithelial and mucosal surfaces is required for survival. The recent discovery of a diverse array of innate lymphoid cells that lie immediately beneath these surfaces has unexpectedly uncovered an entire defense system distinct from the adaptive system essential to protect these barriers. This multilayered design provides a robust system through coupling of two highly complementary networks to ensure immune protection. Here, we discuss the similarities in the hardwiring and diversification of innate lymphoid cells and T cells during mammalian immune responses.

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:

–
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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Our findings address a central, unresolved issue regarding the coordination of innate and adaptive immunities and specialization of ILCs and CD4 T cells. Since the discovery of ILC subsets and appreciation of their functional parallel with T cell subsets (Bando and Colonna, 2016; Huntington et al., 2016; Song et al., 2015; Spits et al., 2013), it has been unclear what functions are unique to each immune cell population. Here, we find that despite their critical role in restraining bacterial colonization over the early course of enteropathogenic bacterial infection, ILC3s—and other IL-22-producing innate immune cells—induce weak STAT3 signaling that is limited to surface IECs.
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View full text

Innate lymphoid cells: parallel checkpoints and coordinate interactions with T cells

Highlights

Introduction

Section snippets

IL-15 is a common key factor for NK cells, ILC1 and CD8+ T cells

Articulation of the functions of ILC2s and Th2s

Redundancy and complementarity of ILC3 and T cells

Concluding remarks

Conflict of interests

References and recommended reading

Acknowledgments

J Immunol

Nat Immunol

Immunity

Blood

J Immunol

Nat Immunol

Nature

Immunity

Proc Natl Acad Sci U S A

Immunity

Nat Immunol

Int Immunol

Nature

J Exp Med

Immunity

J Immunol

Nature

Science

Science

Genome Biol

Innate lymphoid cells – a proposal for uniform nomenclature

Nat Rev Immunol

Immunological Genome C: Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets

Nat Immunol

Perforin and granzymes: function, dysfunction and human pathology

Nat Rev Immunol

Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1

Nat Immunol

The unconventional expression of IL-15 and its role in NK cell homeostasis

Immunol Cell Biol

STAT5-mediated signals sustain a TCR-initiated gene expression program toward differentiation of CD8 T cell effectors

J Immunol

Active STAT5 regulates T-bet and eomesodermin expression in CD8 T cells and imprints a T-bet-dependent Tc1 program with repressed IL-6/TGF-beta1 signaling

J Immunol

Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

Nat Commun

Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1

Nature

IL-15 trans-presentation promotes human NK cell development and differentiation in vivo

J Exp Med

Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells

J Exp Med

IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response

Blood

Cutting edge: naive T cells masquerading as memory cells

J Immunol

Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation

J Exp Med

NK cell development, homeostasis and function: parallels with CD8(+) T cells

Nat Rev Immunol

Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells

J Exp Med

The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells

Nat Immunol

mTORC1 and mTORC2 selectively regulate CD8(+) T cell differentiation

J Clin Invest

Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells

Immunity

Differentiation of Type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages

Cell

A committed precursor to innate lymphoid cells

Nature

Identification of pre- and postselection TCRalphabeta+ intraepithelial lymphocyte precursors in the thymus

Immunity

IL-15 is a common key factor for NK cells, ILC1 and CD8⁺ T cells