ReviewHuman natural killer cell development in secondary lymphoid tissues
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.).
References (71)
- et al.
Lymphocyte development from hematopoietic stem cells
Curr Opin Genet Dev
(2001) - et al.
Identification of the earliest NK-cell precursor in the mouse BM
Blood
(2011) - et al.
Identification of the earliest natural killer cell-committed progenitor in murine bone marrow
Blood
(2011) - et al.
Differentiation of natural killer (NK) cells from human primitive marrow progenitors in a stroma-based long-term culture system: identification of a CD34+7+ NK progenitor
Blood
(1994) - et al.
A human CD34(+) subset resides in lymph nodes and differentiates into CD56bright natural killer cells
Immunity
(2005) - et al.
Education of human natural killer cells by activating killer cell immunoglobulin-like receptors
Blood
(2010) - et al.
Target recognition-induced NK-cell responses
Blood
(2010) - et al.
Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset
Blood
(2001) - et al.
CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity
Blood
(2003) Human natural killer cells
Blood
(2008)
CD94 surface density identifies a functional intermediary between the CD56bright and CD56dim human NK-cell subsets
Blood
cell phenotypes: multiple changing of faces of an adapting, developing cell
Molecular Immunology
Flt3 ligand promotes the generation of a distinct CD34(+) human natural killer cell progenitor that responds to interleukin-15
Blood
The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development
Blood
Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells
Blood
IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells
Immunity
a novel mechanism regulating IL-15 delivery and responses
Immunol Lett
Transregulation of memory CD8 T-cell proliferation by IL-15Ralpha+ bone marrow-derived cells
Blood
The common gamma-chain for multiple cytokine receptors
Adv Immunol
Enrichment of interleukin-2-responsive natural killer progenitors in human bone marrow
Blood
Coordinated acquisition of inhibitory and activating receptors and functional properties by developing human natural killer cells
Blood
Interleukin-1beta selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue
Immunity
Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH 17 cytokine interleukin-22
Blood
Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells
Blood
Developmental programming of natural killer and innate lymphoid cells
Curr Opin Immunol
Transcriptional control of natural killer cell development and function
Adv Immunol
Development and function of group 2 innate lymphoid cells
Curr Opin Immunol
Multifaceted roles of interleukin-7 signaling for the development and function of innate lymphoid cells
Semin Immunol
Location and cellular stages of natural killer cell development
Trends Immunol
What does it take to make a natural killer?
Nat Rev Immunol
Development of human lymphoid cells
Annu Rev Immunol
Developmental pathways that generate natural-killer-cell diversity in mice and humans
Nat Rev Immunol
In vivo developmental stages in murine natural killer cell maturation
Nat Immunol
Genesis of human oncolytic natural killer cells from primitive CD34+CD33- bone marrow progenitors
J Immunol
Defining early human NK cell developmental stages in primary and secondary lymphoid tissues
PLoS One
Cited by (106)
Natural killer cells immunosenescence and the impact of lifestyle management
2023, Biochemical and Biophysical Research CommunicationsNatural killer cells in aging and age-related diseases
2023, Neurobiology of DiseasePan-HDAC inhibitors augment IL2-induced proliferation of NK cells via the JAK2-STAT5B signaling pathway
2023, International ImmunopharmacologyNatural Kills Cells
2022, Encyclopedia of Infection and ImmunityActivated natural killer cells predict poor clinical prognosis in high-risk B- and T-cell acute lymphoblastic leukemia
2021, BloodCitation Excerpt :Reduced cytotoxicity of ALL NK cells suggests that production of cytolytic NK effectorcells is perturbed in ALL patients. Human NK cells mature from a less cytotoxic CD56brightCD16− stage to a highly cytotoxic CD56dimCD16+ stage.58-62 Therefore, we postulated that frequencies of CD56bright and CD56dim NK cells are perturbed in ALL.
Tumor infiltrating NK cell (TINK) subsets and functional molecules in patients with breast cancer
2021, Molecular Immunology