Elsevier

Seminars in Immunology

Volume 26, Issue 2, April 2014, Pages 132-137
Seminars in Immunology

Review
Human natural killer cell development in secondary lymphoid tissues

https://doi.org/10.1016/j.smim.2014.02.008Get rights and content

Highlights

  • In vivo cellular stages of human natural killer (NK) cell development are reviewed.

  • Human NK cell development in secondary lymphoid tissues is presented.

  • Future directions in the field of human NK development are discussed.

  • Distinctions between NK precursors and other innate lymphocytes are discussed.

  • Potential interactions between NK precursors and other immune cells are discussed.

Abstract

For nearly a decade it has been appreciated that critical steps in human natural killer (NK) cell development likely occur outside of the bone marrow and potentially necessitate distinct microenvironments within extramedullary tissues. The latter include the liver and gravid uterus as well as secondary lymphoid tissues such as tonsils and lymph nodes. For as yet unknown reasons these tissues are naturally enriched with NK cell developmental intermediates (NKDI) that span a maturation continuum starting from an oligopotent CD34+CD45RA+ hematopoietic precursor cell to a cytolytic mature NK cell. Indeed despite the detection of NKDI within the aforementioned tissues, relatively little is known about how, why, and when these tissues may be most suited to support NK cell maturation and how this process fits in with other components of the human immune system. With the discovery of other innate lymphoid subsets whose immunophenotypes overlap with those of NKDI, there is also need to revisit and potentially re-characterize the basic immunophenotypes of the stages of the human NK cell developmental pathway in vivo. In this review, we provide an overview of human NK cell development in secondary lymphoid tissues and discuss the many questions that remain to be answered in this exciting field.

Introduction

The natural killer (NK) cell is the prototypic innate lymphoid cell (ILC) whose functional capabilities have evolved to provide direct antimicrobial and antitumor protection as well as indirect immunomodulaton through the production of soluble chemokines and cytokines. NK cells are important if not necessary in a variety of clinical settings, and gaining a comprehensive understanding of how these cells are derived in humans can facilitate the development of targeted therapies to boost NK cell effector function for patients with cancer and/or immune deficiency, can allow us to better evaluate the downstream effects of therapeutic interventions, and can also provide insights into how NK cells undergo malignant transformation.

Though it was discovered more than twenty years ago that human NK cells can be derived in vitro from purified CD34+ hematopoietic precursor cells (HPC), the in vivo NK cell developmental pathway has remained somewhat of a mystery in relative comparison to the pathways for B cell and T cell development [1]. For decades it was generally accepted that NK cells develop exclusively within the bone marrow (BM) similar to most other leukocyte populations other than T cells [2], [3]. BM ablation results in NK cell deficiency in mouse models, and human NK cells may be derived in vitro from BM-derived CD34+ HPC on BM-derived stroma or in BM stroma-derived cytokines [4], [5], [6], [7], [8], [9]. Human BM has also recently been shown to contain CD34 NK cell developmental intermediates (NKDI) [10]. Interestingly, NK cell precursors are normally detected in the circulation, and recent data indicate that specific CD34+ NK cell precursors are selectively enriched in extramedullary tissues where unique subsets of mature NK cells reside, suggesting that the latter may derive locally in situ [11]. As the body has evolved to generate millions of NK cells that are self-tolerant yet capable of substantial tissue destruction and immunomodulation, the notion that NK cells may develop in multiple microenvironments carries important and interesting implications regarding how this process may be regulated in vivo.

Within the last ten years, numerous studies from multiple groups have demonstrated that human NKDI are naturally and selectively enriched in extramedullary tissues including the thymus, peripheral lymph nodes, gastrointestinal track, tonsils, gravid uterus, and liver. Interestingly, these NKDI are not only enriched in the aforementioned tissues, they may also provide some immune function en route to their full development into cytolytic NK cells. Here we provide an overview of NKDI and their development in human secondary lymphoid tissues (SLT).

Section snippets

Human natural killer cell developmental intermediates (NKDI) in SLT

To date there are no known surface antigens that are entirely specific to the human NK cell lineage. By convention, NK cells are minimally defined as lineage (Lin)CD56+ lymphocytes, with “lineage” markers often including CD3 (for T cells), CD19 or CD20 (for B cells), and CD14 (for monocytes). Other pan-NK cell markers, such as NKp46, are typically selectively expressed on normal blood NK cells, but in humans even this marker is rarely expressed on some reactive or neoplastic T cells as well as

Cell intrinsic and extrinsic factors regulating human NK cell development in SLT

Despite a relatively clear view of the NK cell maturation continuum within SLT, the internal and external regulatory mechanisms controlling this process in SLT are largely unknown. IL-15, which is produced by antigen-presenting cells in the T cell interfollicular regions of SLT, is a key external factor that supports NK cell development in SLT. However, whether developing NK cells have access to this membrane-bound ligand throughout their development or whether they receive IL-15 at certain

Challenges in studying human NK cell development in SLT and future directions

One of the major caveats in studying human NK cell development, especially within SLT, is the fact that these aforementioned populations may have the capacity to traffic in and out of the tissues. Therefore, when NKDI from a given tissue are evaluated by flow cytometry, it is impossible to know which, if any, NK cells actually matured in that tissue. Moreover, when stage 4 and stage 5 cells are evaluated ex vivo, one cannot be sure that these cells do not represent activated mature NK cells

Acknowledgements

The authors would like to thank Steven Scoville and Karen Keller for their assistance in generating figures. We apologize for those researchers whose work cannot be cited due to limited space. This review is supported by grants from NCI (CA095426, CA163205, CA16058 and CA068458 to M.A.C. and CA155521 to J.Y.), a 2012 scientific research grant from the National Blood Foundation (to J.Y.), and an institutional research grant (IRG-67-003-47) from the American Cancer Society (to J.Y.).

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