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Histology, Natural Killer Cells
Masum Rahman; Bruno Bordoni.
In this Page
Author Information and Affiliations Introduction
Last Update: February 6, 2023.
Issues of Concern

Introduction Go to: Structure

Function
Natural killer or NK cells are a sub-population of Large Granular
Lymphocytes (LGLs) which arise from a common NK/T-cell progenitor. Histochemistry and Cytochemistry

Accumulating evidence indicates that NK cells can develop and mature both Microscopy, Light
in the bone marrow and secondary lymphoid tissues (SLTs) including tonsils,
Microscopy, Electron
spleen, and Lymph nodes (LNs)[1]. In the innate immune system, NK cells
Pathophysiology
participate in early cytotoxic responses against viruses, parasites, microbial
pathogens, as well as tumor immunosurveillance. Also, their protective and Clinical Significance
pathogenic roles have been more defined in the development of autoimmune Review Questions
diseases such as systemic lupus erythematosus, type I diabetes mellitus, and
References
autoimmune liver disease[2]. NK cell's function is regulated by various
activating or inhibitory receptors. These germ-line encoded immunoreceptors
on the surface of NK cells sense nonspecific alterations of self cells caused by Bulk Download
cellular stress, infections, or malignant transformation[3]. In contrast, B and T Bulk download StatPearls data from FTP
lymphocytes in the adaptive arm, undergo gene rearrangement to generate
surface receptors and mediate the antigen-specific immune responses [4][5].
Related information
While encountering normal cells, inhibitory receptors override activating
PMC
receptors. However, molecular changes on the cell surface due to viral
infection or tumor formation can stimulate the activating receptors. Upon PubMed

activation, NK cells release granzyme, perforin, effector molecules of the

TNF family, and Fas-ligand to induce apoptosis of the target cells. In addition,
Similar articles in PubMed
NK cells synthesize and release other cytokines and chemokines such as Il-10,
Review The Role of Natural Killer Cells in
gamma-interferon, GM-CSF to recruit other immune effector cells to the Autoimmune Diseases.[Front Immunol. 2021]

https://www.ncbi.nlm.nih.gov/books/NBK565844/[9/11/2023 2:44:45 PM]

Histology, Natural Killer Cells - StatPearls - NCBI Bookshelf

target site. NK cells also exhibit antibody-dependent cell cytotoxicity against

The abundant NK cells in human secondary
cells or target antigens which are marked with specific antibodies. Recently, [J Immunol.
lymphoid tissues require activation to 2004]
therapeutic applications modulating the inhibition-activation dynamic of NK
The participation of the Fas-mediated
cells have been developed for multiple conditions including cancer, [Cancer
cytotoxic Immunol
pathway Immunother.
by natural killer cells1997]
is
autoimmune disease, diabetes, etc.[6]
Receptors and lytic mediators regulating
[Jleukemic
anti-tumor activity by the Leukoc Biol.
killer2005]
T
Issues of Concern Go to:
Review The Impact of HLA Class I-Specific
Natural Killer cells represent the third lymphocyte population (Following T [Front Immunol.
Killer Cell Immunoglobulin-Like 2016]
Receptors
and B cells), and they play essential roles in the frontline's defense of the See reviews...
innate immune system. The term natural killer suggests that these cells can
See all...
kill the target cells without pre-stimulation. In contrast to other immune cells,
which demand a considerable period of time to induce their cytolytic activity,
NK cells provide ready-to-kill machinery in the immune system.   Recent Activity
Turn Off Clear
These cells play various roles in several organ systems; for instance, there is Histology, Natural Killer Cells -
emerging evidence linking NK cells with the development of autism spectrum StatPearls
disorder. The lower degrees of NK cells infiltration in solid tumors correlate
See more...
with the favorable prognosis. In addition, excessive stimulation of NK cells
promotes cell senescence in tissues, laying the foundations for aging. NK cells
are important for the body's salutogenic response in dealing with various
physiological and non-physiological stimuli throughout life.

Structure Go to:

Morphologically, NK cells are large, granular lymphocytes that are defined by

expression of CD56 and CD16 and lack the common T cell marker, CD3, and
T cell receptor (TCR) in humans. They constitute 5-15% of the total
population of peripheral mononuclear circulating lymphocytes [7]. NK cells,
dendritic cells, B and T lymphocytes are derived from single lymphoid
progenitor cells.

A variety of activating or inhibitory receptors have been demonstrated on the

surface of NK cells as their immunoreceptor. Inhibitory receptors have
cytoplasmic tyrosine-based inhibition motifs and recognize self major
histocompatibility complex class I (MHC I) molecules expressed by most of
the nucleated cells. However, activating receptors recognize the ligands
exhibited by pathological cells and interact with cell signaling pathways to
initiate effector activities. Examples of their activating receptors are CD16,
NKp30, NKp44, NKp46, NKG2C/CD94, and NKG2D/CD94. NK cells have
distinct cytoplasmic granules that are structurally and functionally similar to
lysosomes, hence called “secretory lysosomes.” These granules have a
bilayered membrane that separates their lytic content from the cytoplasm. [8]

Function Go to:

Natural killer cells' effector functions are tightly regulated by the balance of

https://www.ncbi.nlm.nih.gov/books/NBK565844/[9/11/2023 2:44:45 PM]

Histology, Natural Killer Cells - StatPearls - NCBI Bookshelf

inhibitory and activating receptors and downstream intracellular signaling

cascades of these receptors. NK cells were originally identified in the
1970s[9][10], although the mechanism by which they distinguish healthy cells
from virus-infected or tumor cells was not fully known for years. First, the
results of research on murine NK cells demonstrated that NK cells are able to
detect and eliminate lymphoma cells that lost the expression of MHC I,
whereas MHC I expressing tumor cells are unaffected by NK cells[3]. This
led to the idea of missing self in the activation of NK cells, particularly in
their anti-tumor activity. In physiological conditions, most of the circulating
NK cells are in the resting state as their inhibitory receptors interact with
MHC I on the healthy cells and this accounts for exhibiting self-tolerance
(Fig.1a). Almost every healthy cell expresses MHC I molecules, a potential
ligand for inhibitory NK cell receptors, However, MHC I molecules are
downregulated upon viral infection and tumor transformation (missing self),
exerting subthreshold inhibitory signaling to the NK cells, moving their
balance toward the activated state (Fig.1b). In addition, upregulation of NK
cells activating receptors occurs in stressed or damaged cells resulting in
targeting these cells for the cytolytic activity of NK cells (Fig.1c). Interaction
between CD16 on NK cells with antigens expressed on tumor cells
causes antibody-dependent cell-mediated cytotoxicity (ADCC) tumor cell
lysis by NK cells(Fig.1d). [11][12][13][14][15]

NK cells can kill tumor cells without previous sensitization. They directly kill
tumor cells by releasing lytic granules that contain granzyme and perforin. NK
cells, together with cytotoxic CD8+ T lymphocytes, generate immunity
against virus-infected and tumor cells. In most circumstances, tumor cells
downregulate their MHC I to escape from cytotoxic T cells. However, the
lower expression of MHC I make tumor cells susceptible to lysis by NK
cell.[16]

Histochemistry and Cytochemistry Go to:

NK cells are considered the equivalent of CD8 positive T lymphocytes in the

innate immune system and multiple cell markers are used for their
characterization in immunocytochemistry staining. Natural killer cells are
usually classified as CD3 negative and CD56 positive cells and subdivided
into CD56dim and CD56bright groups. CD56dim and CD56bright subsets are
defined based on the density of CD56 and have distinct functional attributes.

About 90% of circulating and spleen natural killer cells are CD56dim, CD16
positive, and express perforin. CD56dim cells mainly perform a cytotoxic
action and CD16 mediates ADCC. In comparison, NK cells in lymph nodes
(LNs) and peripheral lymphoid organs (e.g., tonsils) are CD56bright and
CD16 negative. CD56 bright cells are mainly cytokine secreting cells and
have the capacity to produce several cytokines, including IFN-γ (gamma-
interferon) upon stimulation.[16][17][18]

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Histology, Natural Killer Cells - StatPearls - NCBI Bookshelf

Microscopy, Light Go to:

Natural killer cells present a distinct group of circulating lymphocytes on the

peripheral blood smear. On Wright-Giemsa-staining, they are visible as large
granular lymphocyte morphology. They possess large nuclei containing coarse
chromatin and prominent nuclei. Their abundant basophilic cytoplasm
contains plenty of azurophilic granules that are negative for peroxidase
staining.[19]

Microscopy, Electron Go to:

NK cells are large and exhibit various shapes and express microvilli more
prominently in the area of effector-to-target contact. At the same time,
microvilli are scant cell surface in the absence of target cells. Membranes are
not extensively fused in the region of target and effector cell contact.

NK cells have structurally distinct granules that consist of two different

compartments. The outer compartment includes the lysosome-associated
phosphatase acid enzymes and trimetaphosphatase. No enzymatic activities
associated with the inner compartment have been identified. At the time of
degranulation, a limited area of the cytoplasm exhibits vacuole-like areas
possessing granules and apparent granular debris. Degranulation appears to be
implicated in NK cells' cytotoxic activity. Convoluted nuclei with distinctive
polarity against the dense granules and pseudopodia are typical. In the
cytoplasm, both Mitochondria and polysomes are observed.[19][20]

Pathophysiology Go to:

In addition to NK cell roles in defense against viral infections and tumor

immunosurveillance, they have been linked to several other diseases including
asthma [21], inflammatory bowel disease [22], and autoimmune diseases [23].
Advancements in understanding the pathophysiology of NK cells resulted in
the development of new therapeutic options and treatments. For instance, NK
cells are found in the pancreas of patients with diabetes type I, and they
enhance the disease development. Reducing the NK cell activation using
specific blocking antibodies will prevent further disease progression.[6]

Clinical Significance Go to:

NK cells are essential components of innate immunity. Although their

function may be compromised in many primary immune deficiency disorders,
rare isolated Natural Killer cell deficiency syndromes may also occur. There
are two potential varieties of NK cell deficiency: (1) the classical natural killer
cell deficiency (CNKD) and (2) functional natural killer cell
deficiency(FNKD).[24][25]

CNKD reflects the significant absence of NK cells among peripheral blood

mononuclear cells and fewer than 1% of NK cells in peripheral blood should

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Histology, Natural Killer Cells - StatPearls - NCBI Bookshelf

be present in a minimum of three independent tests separated by one month to

establish this diagnosis. Unlike CNKD, patients with FNKD have NK cells
found in their peripheral blood within the spectrum of age-specific average
values; however, permanently deficient in their functions. Both CNKD and
FNKD patients are highly susceptible to human papillomavirus (HPV), herpes
simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV),
varicella-zoster virus (VZV) infection.[24][26][27]

The prognostic value of NK cells infiltrating solid tumors has attracted

considerable attention in clinical practice. Several independent studies have
demonstrated that higher levels of NK cell markers such as CD56 and NKp46
in solid tumors correlate with favorable prognosis and overall survival
rate [28][29][30]. However, further research is necessary to establish a scoring
system including information from tumor type, clinical staging, pathological
grading, etc. The clinical development of NK cell-based cancer therapy
provided promising results recently. The NK cell-based clinical trials
presented a desirable safety profile and efficacy in hematologic malignancies
and solid tumors. [31][32][33]

Review Questions Go to:

Access free multiple choice questions on this topic.

Comment on this article.

References Go to:

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Disclosure: Masum Rahman declares no relevant financial relationships with ineligible

companies.

Disclosure: Bruno Bordoni declares no relevant financial relationships with ineligible

companies.

Copyright © 2023, StatPearls Publishing LLC.

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