Interactions between innate and adaptive lymphocytes

Abstract

Innate lymphocytes - including natural killer cells and the recently discovered innate lymphoid cells - have crucial roles during infection, tissue injury and inflammation. Innate signals regulate the activation and homeostasis of innate lymphocytes. The contribution of the adaptive immune system to the coordination of innate lymphocyte responses is less well understood. In this Opinion article, we review our current understanding of the interactions between adaptive and innate lymphocytes, and propose a model in which T cells of the adaptive immune system function as antigen-specific sensors for the activation of innate lymphocytes to amplify and instruct local immune responses. We highlight the potential roles of regulatory and helper T cells in these processes, and discuss major questions in the emerging area of crosstalk between adaptive and innate lymphocytes.

Figure 1. Innate and adaptive lymphocyte subsets

A common lymphoid progenitor (CLP) in the bone marrow gives rise to precursors of T cells, NK cells and innate lymphoid cells (ILC). T cell precursors enter the thymus where they develop into naive T cells that harbor rearranged antigen-receptors and then seed the secondary lymphoid organs. Once stimulated by cognate antigen and polarizing innate cytokines, T cells undergo effector differentiation guided by key transcription factors and acquire the capacity to secret “hallmark” cytokines that orchestrate immune responses against intracellular pathogens (IFNγ), extracellular parasites (IL-4, -5, -13) or bacteria and fungi (IL-17). These T cells are frequently found in non-lymphoid organs as short-lived effector cells whereas some of them can become long-lived resident memory cells. Innate lymphocytes have been categorized based on their expression pattern of the aforementioned “master” transcription factors and “hallmark” cytokines that resemble T cell subsets. In contrast to T cells, ILC differentiate from the CLP through a common precursor in the bone marrow and developmentally acquire an “effector phenotype” reflected by their ability to seed peripheral organs and to produce the above-mentioned “helper” cytokines without further differentiation. Regulatory T cells are characterized by the expression of the lineage-specifying transcription factor FOXP3 (not depicted). Regulatory T cells can co-express FOXP3 and transcription factors specifying distinct helper T cell types which enables suppression of the respective classes of the immune response . So far, innate lymphocytes have not been found to express FOXP3. Not depicted are follicular helper T cells and a recently described ILC subset, both of which interact with B cells . Lymphoid tissue inducer (LTi) cells represent a subset of innate lymphocytes that interacts with stromal cells to facilitate the development of lymphoid organs. TH = T helper cell, NKP = NK cell precursor, CILP = Common ILC precursor, CHILP = Common “helper-like” ILC precursor.

Figure 2. Interactions of innate lymphocytes

(A) Innate lymphocytes interact with three major cell types: non-hematopoietic stromal and epithelial cells, myeloid cells and other lymphocytes. Many of these interactions are bidirectional. For example, epithelial derived alarmins can activate ILCs to secrete factors that stimulate epithelial regeneration. With the exception of NK cells, little is known about the receptors and ligands that mediate contact-dependent interactions of innate lymphocytes. While the communication of innate lymphocytes with myeloid cells is relatively well understood, much needs to be learned about the interactions of innate lymphocytes with other lymphocytes, including both innate and adaptive lymphocytes. In this regard, part (B) highlights known and putative interactions of innate lymphocytes with T cells. NK cells can limit immunopathology during antiviral T cell responses through TRAIL- or NKG2D-mediated killing of T cells. ILC3 can process antigens and present them on MHC class II molecules to limit pathological T cell immunity at mucosal sites. NK cells and ILCs produce classical T helper cell cytokines that are known to modulate the numbers and activity of myeloid cells, including neutrophils, eosinophils, macrophages and DCs, but can also act directly on T cells. Local conditioning of the cytokine milieu by innate lymphocytes may, therefore, directly and/or indirectly contribute to the initiation and polarization of the adaptive response. Similarly, the production of immunosuppressive cytokines (e.g. IL-10 or TGFβ) by innate lymphocytes may directly and/or indirectly modulate T cell responses. Part (C) summarizes the putative mechanisms by which T cells could modulate innate lymphocytes. T cells and innate lymphocytes may compete for common resources, such as growth factors and metabolites. In this regard, T cell-derived IL-2 can “help” the expansion and activation of NK cells, and potentially other subsets of ILC. T_Reg cells can restrain this cellular cross-talk by limiting T cell activation, or by competing with innate lymphocytes for IL-2 (see also Figure 3). T cell secretion of classical helper cytokines or immunosuppressive cytokines may directly and/or indirectly, via the modulation of myeloid cells, instruct innate lymphocyte responses. T cells and ILC can also engage in T cell receptor/MHC class 2 dependent interactions that may modulate the function of both cell types.

Figure 3. A model for IL-2-dependent adaptive–innate lymphocyte crosstalk

A growing body of evidence suggests cooperation between innate and adaptive lymphocytes. In this context, T cells might function as antigen-specific sensors that amplify local immune responses by recruiting and modulating innate lymphocytes. The cytokine IL-2 provides one example of how a tri-cellular crosstalk between T cells, T_Reg cells and innate lymphocytes can be established. In this regard, local inflammatory mediators could function to pre-activate the three cell types, and to render innate lymphocytes more perceptive to IL-2, for example through the upregulation of CD25. Once T cells encounter their cognate antigens (presented e.g. by epithelial or myeloid cells, or potentially by ILC) they secrete IL-2 (and other soluble factors) that can co-activate innate lymphocytes, and decrease their activation threshold. Such a response-modulating function of T cells would function to “spread” the antigen-specific signal to surrounding innate lymphocytes, to amplify local cytokine production, increase the secretion of tissue-protective factors, and optimize NK cell-mediated immune surveillance for “missing-self” and stress-induced ligands. Regulatory T cells could balance this adaptive–innate crosstalk and prevent excessive activation of ILCs by competing for IL-2. Alternatively, IL-2 may activate T_Reg cells to directly inhibit innate lymphocytes, or to synergize with innate lymphocytes in maintaining tissue function and homeostasis.