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An adaptive natural killer (NK) cell or memory-like NK cell is a specialized
natural killer cell Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repres ...
that has the potential to form
immunological memory Immunological memory is the ability of the immune system to quickly and specifically recognize an antigen that the body has previously encountered and initiate a corresponding immune response. Generally, these are secondary, tertiary and other subs ...
. They can be distinguished from cytotoxic NK (cNK) cells by their receptor expression profile and epigenome. Adaptive NK cells are so named for properties which they share with the
adaptive immune system The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
. Though adaptive NK cells do not possess antigen specificity, they exhibit dynamic expansions of defined cell subsets, increased proliferation and long-term persistence for up to 3 months ''in vivo'', high
IFN-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
production, potent cytotoxic activity upon ''ex vivo'' restimulation, and protective memory responses. Adaptive NK cells have been identified in both humans and mice. Persistent adaptive NK populations have been reported during
viral infection A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells. Structural Characteristics Basic structural characteristics, s ...
, contact hypersensitivity reactions, and after stimulation by pro-inflammatory cytokines or activating receptor pathways. IL-12, IL-18, and IL-15 contribute to the development of adaptive NK cells by priming NK cells prior to immune stimulation.


Origin

Human adaptive NK cells in peripheral blood are likely derived from cNK cells expressing low levels of
CD56 Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discover ...
, as CD56dim cNK cells are more likely to express
killer-cell immunoglobulin-like receptor Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. At least 15 genes and 2 pseudogenes encoding KIR map ...
s (KIRs) and/or CD94/NKG2C. These surface molecules are required for antigen sensing during infection. Some evidence exists for tissue-resident adaptive NK cells in the liver, where a small population of
CD49a Integrin alpha-1 also CD49a is an integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular ...
+
NKG2C NKG or nkg may refer to: * NKG, the IATA code for Nanjing Lukou International Airport, Jiangsu, China * nkg, the ISO 639-3 code for Nekgini language, Papua New Guinea {{Disambiguation ...
+ NK cells has been shown to emerge in response to
human cytomegalovirus ''Human betaherpesvirus 5'', also called human cytomegalovirus (HCMV), is species of virus in the genus ''Cytomegalovirus'', which in turn is a member of the viral family known as ''Herpesviridae'' or herpesviruses. It is also commonly called ...
infection. These cells differ from the predominant population of
CD49a Integrin alpha-1 also CD49a is an integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular ...
CD49e Integrin alpha-5 is a protein that in humans is encoded by the ''ITGA5'' gene. The product of this gene belongs to the integrin alpha chain family. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. ...
NK cells in the liver by their gene expression. Signals transmitted through the
IL-12 receptor Interleukin 12 receptor is a type I cytokine receptor, binding interleukin 12. It consists of beta 1 Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphab ...
combined with
CD2 CD2 (cluster of differentiation 2) is a cell adhesion molecule found on the surface of T cells and natural killer (NK) cells. It has also been called T-cell surface antigen T11/Leu-5, LFA-2, LFA-3 receptor, erythrocyte receptor and rosette rece ...
and MHC class I-binding receptor provide a three-prong stimulation responsible for promoting the
epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are " ...
and
phenotypic In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
modifications that occur in association with adaptive NK cell differentiation.


Epigenetic regulation

NK cells essentially "remember" the previous effects of cytokines. NK cells pre-activated by IL-12/ 15/ 18 transfer their enhanced
IFN-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
producing capacity to daughter cells.
HCMV ''Human betaherpesvirus 5'', also called human cytomegalovirus (HCMV), is species of virus in the genus ''Cytomegalovirus'', which in turn is a member of the viral family known as ''Herpesviridae'' or herpesviruses. It is also commonly called ...
-associated
NKG2C NKG or nkg may refer to: * NKG, the IATA code for Nanjing Lukou International Airport, Jiangsu, China * nkg, the ISO 639-3 code for Nekgini language, Papua New Guinea {{Disambiguation ...
+ adaptive NK cells and IL-12/ 15/ 18 pre-activated NK cells have been detected to have an epigenetic imprint, for instance, the
demethylated Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen ato ...
CNS1 region of the IFNG gene, which in turn can lead to a remarkable stability of the
IFN-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
-producing phenotype even after adoptive transfer. Both IL-12 and IL-18 are required for the pronounced
demethylation Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen ato ...
of the CNS1 region, whereas IL-15 might serve as a survival factor. In addition to the IFNG gene,
NKG2C NKG or nkg may refer to: * NKG, the IATA code for Nanjing Lukou International Airport, Jiangsu, China * nkg, the ISO 639-3 code for Nekgini language, Papua New Guinea {{Disambiguation ...
+ adaptive NK cells also showed
CpG CpG can be: * CpG site - methylated sequences of DNA significant in gene regulation * CpG Oligodeoxynucleotide - unmethylated sequences of DNA that have immunostimulatory properties *CpG island The CpG sites or CG sites are regions of DNA wher ...
demethylation Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen ato ...
of the PRDM1/BLIMP1 and ZBTB32/TZFP genes or hypermethylation of
FCER1G Fc fragment of IgE, high affinity I, receptor for; gamma polypeptide is gamma chain of high affinity IgE receptor The high-affinity IgE receptor, also known as FcεRI, or Fc epsilon RI, is the high-affinity receptor for the Fc region of immun ...
(
Fc fragment The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune ...
of IgE receptor Ig). Pre-activation of NK cells by the cytokines IL-12/ 18 plus IL-15 or by engagement of FcγRIII/CD16 via therapeutic antibodies can induce similar memory-like functions: an enhanced proliferative capacity toward
IL-2 The Ilyushin Il-2 (Russian: Илью́шин Ил-2) is a ground-attack plane that was produced by the Soviet Union in large numbers during the Second World War. The word ''shturmovík'' (Cyrillic: штурмовик), the generic Russian term ...
due to
CD25 Interleukin-2 receptor alpha chain (also called CD25) is the human protein encoded by the ''IL2RA'' gene. The interleukin 2 (IL2) receptor alpha (IL2RA) and beta (IL2RB) chains, together with the common gamma chain (IL2RG), constitute the high-a ...
up-regulation as well as a strengthened responsiveness to restimulation by
tumor cells A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
. Importantly, both memory-like functionalities are antigen-unspecific and mean “remembering” a previous state of increased activation caused by
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in a ...
exposure or stimulation via activating NK cell receptors.


In humans

Unique and expanded adaptive NK cell populations were observed in
peripheral blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in th ...
in humans that have been previously infected with Human Cytomegalovirus (HCMV). These NK cells bear activating MHC class I-binding receptors, typically CD94/NKG2C, demonstrate reduced activation and degranulation in response to activated autologous
T cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell ...
and they are CD56dim CD16+. In comparison to CD56dim cNK cells, adaptive NK cells generally show decreased expression of surface
CD7 CD7 (Cluster of Differentiation 7) is a protein that in humans is encoded by the ''CD7'' gene. Function This gene encodes a transmembrane protein which is a member of the immunoglobulin superfamily. This protein is found on thymocytes and matur ...
,
CD161 Killer cell lectin-like receptor subfamily B, member 1, also known as KLRB1, NKR-P1A or CD161 (cluster of differentiation 161), is a human gene. Function Natural killer (NK) cells are lymphocytes that mediate cytotoxicity and secrete cytokines ...
,
NKp30 Natural cytotoxicity triggering receptor 3 is a protein that in humans is encoded by the ''NCR3'' gene. NCR3 has also been designated as CD337 ( cluster of differentiation 337) and as NKp30. NCR3 belongs to the family of NCR membrane receptors to ...
,
NKp46 Natural cytotoxicity triggering receptor 1 is a protein that in humans is encoded by the ''NCR1'' gene. NCR1 has also been designated as CD335 (cluster of differentiation The cluster of differentiation (also known as cluster of designation or cl ...
, and SIGLEC-7 but demonstrate retained or even higher expression of
CD2 CD2 (cluster of differentiation 2) is a cell adhesion molecule found on the surface of T cells and natural killer (NK) cells. It has also been called T-cell surface antigen T11/Leu-5, LFA-2, LFA-3 receptor, erythrocyte receptor and rosette rece ...
,
CD57 3-beta-glucuronosyltransferase 1 (B3GAT1) is an enzyme that in humans is encoded by the ''B3GAT1'' gene, whose enzymatic activity creates the CD57 epitope on other cell surface proteins. In immunology, the CD57 antigen (CD stands for cluster of di ...
, and CD85j (ILT2, LILRB1). None of these surface marker expression patterns are inherently specific for adaptive NK cells, but together they may help to identify discrete populations of adaptive NK cells. Human adaptive NK cells have the hypomethylated region of
IFN-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
promoter. After stimulation through
CD16 CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRI ...
ligation Ligation may refer to: * Ligation (molecular biology), the covalent linking of two ends of DNA or RNA molecules * In medicine, the making of a ligature (tie) * Chemical ligation, the production of peptides from amino acids * Tubal ligation, a met ...
adaptive NK cells produce large amounts of
IFN-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
and also extensively proliferate. The cytotoxicity of adaptive NK cells remains a constant question in this field. It had been indicated similar or reduced degranulation of
CD107a Lysosomal-associated membrane protein 1 (LAMP-1) also known as lysosome-associated membrane glycoprotein 1 and CD107a (Cluster of Differentiation 107a), is a protein that in humans is encoded by the ''LAMP1'' gene. The human ''LAMP1'' gene is locat ...
as compared to cNK cells after
CD16 CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRI ...
ligation or stimulation with antibody-coated tumor targets. The discovery of memory in the human NK compartment makes us wonder whether it could be harnessed by vaccination. This could be particularly effective in HIV infections where CD4+T cells get rapidly depleted as it provides an alternative where B and T cells cannot be harnessed.


Therapeutic potential

The clinical application of NK cells with memory-like properties can significantly increase the efficiency of these cells and pave the way for the new NK cell-based clinical approaches for the
cancer treatment Cancer can be treated by surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy (including immunotherapy such as monoclonal antibody therapy) and synthetic lethality, most commonly as a series of separate treatments (e.g. ...
. Adaptive NK cells can mediate the enhanced antitumor effects, that may be due to their increased cytotoxicity, high
IFN-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
production capacity, and persistence in large numbers in the host. Clinical use of
allogeneic Allotransplant (''allo-'' meaning "other" in Greek) is the transplantation of cells, tissues, or organs to a recipient from a genetically non-identical donor of the same species. The transplant is called an allograft, allogeneic transplant, or ...
NK cells is promising for the treatment of
leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
. KIR-ligand mismatch has a beneficial effect on the alloreactivity of donor NK cells against recipient
leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
. Besides, it has been shown that the
adoptive transfer Adoptive cell transfer (ACT) is the transfer of cells into a patient. The cells may have originated from the patient or from another individual. The cells are most commonly derived from the immune system with the goal of improving immune functiona ...
of alloreactive NK cells does not cause graft-versus-host disease (GVHD), but instead suppresses
GVHD Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants. White blood cells of the donor's immune system which remain wit ...
.


See also

* Natural killer cell § Adaptive features *
Killer-cell immunoglobulin-like receptor Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. At least 15 genes and 2 pseudogenes encoding KIR map ...
* KLRC2 *
Adoptive cell transfer Adoptive cell transfer (ACT) is the transfer of cells into a patient. The cells may have originated from the patient or from another individual. The cells are most commonly derived from the immune system with the goal of improving immune function ...
*
CD56 Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discover ...
*
Human Cytomegalovirus ''Human betaherpesvirus 5'', also called human cytomegalovirus (HCMV), is species of virus in the genus ''Cytomegalovirus'', which in turn is a member of the viral family known as ''Herpesviridae'' or herpesviruses. It is also commonly called ...
*
IFN-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...


References

{{reflist, 30em Lymphocytes Human cells