ReviewTissue-resident natural killer cells and their potential diversity
Introduction
Several immune cell lineages migrate throughout the body via the circulatory system in search of detrimental insults provoked by pathogenic events, such as invading microorganisms or developing tumors. Once detected, the circulating immune cells stop and respond in secondary lymphoid organs such as the lymph nodes and spleen. What follows subsequently is an orchestrated host immune response, which controls the pathological process by recruiting relevant immune cells to the damaged tissue. In contrast to the well-studied circulating immune cells are tissue-resident immune cells, which already reside in selected organs where they appear to be armed and ready to rapidly respond. However, less is known about the properties of tissue-resident immune cells that seem to be closely related to their counterparts which re-circulate.
Conventional natural killer (cNK) cells are constituents of the innate arm of the immune system [1]. First described on the basis of their inherent capacity to directly kill tumor cells without prior sensitization, NK cells are now known to participate in a wide variety of immune responses, such as viral infections, stem cell transplantation, and pregnancy. In addition, they can respond to pro-inflammatory cytokines by producing interferon-γ (IFN-γ), their signature cytokine, which can impact adaptive immunity. Although classically studied in the mouse spleen, NK cells are also found in organs, such as the thymus and liver [1]. In the thymus, NK cells have been described which are phenotypically different from cNK cells [2]. In the liver, we recently showed that there are two populations of NK cells, one that resembles splenic cNK cells and that recirculates and another that is tissue-resident [3].
In this review we will discuss the developmental, phenotypic, and functional relationships between the splenic cNK, thymic NK cells, and tissue-resident NK (trNK) cells in the liver. We will highlight features of cNK cells that are relevant to understanding the other NK cell subpopulations and we will also describe NK cells found in other organs, such as the uterus, which may include trNK cells. Finally, we will discuss how these NK cells relate not only to one another but to the larger family of innate lymphoid cells (ILCs) [4], [5].
Section snippets
Developmental requirements of cNK cells
The bone marrow (BM) is the site of splenic cNK development and maturation. In the BM, the developmental stages are characterized by acquisition and loss of cytokine receptors, NK cell receptors, and integrins [6], [7], [8]. One of the late maturation markers, DX5 (α2 integrin), is expressed prior to exit out of the BM and is one of the markers of mature splenic cNK cells. Out in the periphery, mature splenic cNK cells can be further distinguished by a loss of CD27 expression [6], [9]. Thus,
Thymic NK cells
Among the lymphoid tissues, the thymus has NK cells with surface marker phenotypes resembling immature cNK cells [2]. Specifically, as compared to splenic cNK cells that are Ly49hi CD11bhi, thymic NK cells are Ly49low CD11blow, like immature BM cNK cells. However, thymic NK cells are CD127+ CD69high unlike resting splenic cNK cells and developing cNK cells in the BM. While the thymic NK cells have not been rigorously tested for selective tissue localization, their relatively unique phenotype as
Tissue-resident NK (trNK) cells
In the liver, a population of NK cells appeared to be similar to immature cNK cells because they express similar surface markers such as NK1.1 and NKp46 and low levels of CD11b [3], [6], [8]. Moreover, they are DX5–and display high levels of TNF-related apoptosis-inducing ligand (TRAIL). This immature phenotype gave the impression that organs such as the liver contained a subpopulation of NK cells that was not fully differentiated. Our recent studies, however, indicate that these liver NK cells
Similarities and differences between NK cell subsets
Based on the detailed descriptions above, there appear to be several distinguishable populations of NK cells. Here we will highlight the major similarities and differences between these NK cell subpopulations in different anatomical locations (Table 1).
Although there are many distinguishing features between the aforementioned NK cell subpopulations, it is relevant to point out their commonalities. All of these NK cells do not depend on recombination activating genes (RAG) to rearrange antigen
Comparison of NK cells and ILCs
The ILCs are a heterogeneous family of cells which belong to the innate immune system [4], [5]. ILCs reside in specialized submucosal areas as the gastrointestinal tract and bronchial pathway in the lungs, where they maintain epithelial integrity, and contain commensal bacteria, and inflammation. The ILCs require the Id2 transcription factor for development, and some express and require CD127 for their maintenance. The ILCs have recently been organized into three major groups (groups 1, 2, and
Conclusions
In summary, trNK cells in the liver are distinct from circulating cNK cells and thymic NK cells in their differential expression of NK cell receptors. Their tissue residency in the sinusoidal space of the liver potentially highlights a special feature that suggests that they have tissue-specific functions, raising the possibility that other organs, such as the uterus, have trNK cells. In addition, these NK cells can be distinguished from ILCs although these distinctions may be challenging as
Acknowledgments
We thank the Yokoyama lab for great discussions. Studies in the Yokoyama laboratory are supported by RO1-AI106561 from the National Institutes of Health. W.M.Y. is an Investigator of the Howard Hughes Medical Institute. D.K.S. is supported by T32 CA009547 from the National Institutes of Health.
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