The document discusses induced innate immunity and the roles of cytokines and chemokines. It can be summarized as follows: 1. Induced innate immunity begins 4-96 hours after exposure to pathogens and involves the recruitment of defense cells through cytokines and chemokines produced in response to pathogen recognition. 2. Cytokines are small proteins released by cells in response to stimuli that induce responses by binding to receptors, acting in autocrine, paracrine, or endocrine manners. Chemokines are a class of cytokines that induce cell migration. 3. Key cytokines and chemokines involved in innate immunity include interleukin-1, interleukin-6, interleukin-12, TNF-α, and interleukin-8. They

1. Induced Innate Immunity
Early induced innate immunity begins 4 - 96 hours after exposure to an infectious agent and
involves the recruitment of defense cells as a result of pathogen-associated molecular patterns or
PAMPs binding to pattern-recognition receptors or PRRs. The induced responses of innate
immunity depends upon the cytokines and chemokines that are produced in response to pathogen
recognition. The macrophage-derived cytokines promote the phagocytic response through
recruitment and production of fresh phagocytes and opsonizing molecules. We also discuss the
role of the cytokines known as interferons, which are induced by viral infection, and at a class of
lymphoid cells, known as natural killer (NK) cells, that are activated by interferons to contribute
to innate host defense against viruses and other intracellular pathogens. The induced innate
responses either succeed in clearing the infection or contain it while an adaptive response develops
[1].
Cytokines
Cytokines are small proteins that are released by various cells in the body, usually in response to
an activating stimulus, and induce responses through binding to specific receptors.
Mode of action
1. Autocrine manner: they can act in autocrine manner, affecting the behavior of the cell that
releases the cytokine.
2. Paracrine manner: they can act in a paracrine manner, affecting the behavior of adjacent
cells.
3. Endocrine manner: Some cytokines can act in an endocrine manner, affecting the behavior
of distant cells.
Chemokines
Chemokines are a class of cytokines that have chemoattractant properties, inducing cells with the
appropriate receptors to migrate toward the source of the chemokine. The cytokines secreted by
macrophages in response to pathogens.
Examples

2.  Interleukin-1 (IL-1),
 Interleukin-6 (IL-6),
 Interleukin-12 (IL-12),
 TNF-α,
 Chemokine interleukin-8 (IL-8).
Three major structural families: There are three major structural families.
1. The hematopoietin family
This family includes growth hormones as well as many interleukins with roles in both
adaptive and innate immunity. For example IL-6
2. The TNF family
TNF-α is a part of this family which functions in both innate and adaptive immunity.
3. Chemokine family
This family includes some membrane-bound members, for example IL-1 and IL-2.
All these three families have important local and systemic effects that contribute to both innate
and adaptive immunity [2, 3].
Function of chemokines
Chemokines function mainly as chemoattractant for leukocytes, recruiting monocytes, neutrophils,
and other effector cells from the blood to sites of infection. They can be released by many different
types of cell and serve to guide cells involved in innate immunity and also the lymphocytes in
adaptive immunity. Some chemokines also function in lymphocyte development, migration, and
angiogenesis (the growth of new blood vessels).
Classification of chemokines
Chemokines fall mainly into two related but distinct groups
1. The CC chemokines
The CC chemokines in humans are mostly encoded in one region of chromosome 4, have
two adjacent cysteine residues in their amino-terminal region. CC chemokines bind to CC
chemokine receptors, of which there are nine so far, designated CCR1-9. . The CC

3. chemokines promote the migration of monocytes or other cell types. An example is
macrophage chemoattractant protein-1 (MCP-1).Other CC chemokines such as RANTES
may promote the infiltration into tissues of a range of leukocytes including effector T cells.
The only known C chemokine (with only one cysteine) is called lymphotactin and is
thought to attract T-cell precursors to the thymus.
2. The CXC chemokines
CXC chemokines, the genes for which are mainly found in a cluster on chromosome 17,
have an amino acid residue between the equivalent two cysteines.CXC chemokines bind
to CXC receptors; there are five of these, CXCR1-5. These receptors are expressed on
different cell types; in general, CXC chemokines with a Glu-Leu-Arg (ELR) tripeptide
motif immediately before the first cysteine promote the migration of neutrophils. IL-8 is
an example of this type of chemokine. Other CXC chemokines that lack this motif, such as
the B lymphocyte chemokine (BLC), guide lymphocytes to their proper destination.
3. The CX3C chemokines
A newly discovered molecule called fractalkine is unusual in several ways: it has three
amino acid residues between the two cysteines, making it a CX3C chemokine; it is
multimodular; and it is tethered to the membrane of the cells that express it, where it serves
both as a chemoattractant and as an adhesion protein.
Role of chemokines in cell recruitment
The role of chemokines such as IL-8 and MCP-1 in cell recruitment is twofold.
First, they act on the leukocyte as it rolls along endothelial cells at sites of inflammation,
converting this rolling into stable binding by triggering a change of conformation in the adhesion
molecules known as leukocyte integrins. This allows the leukocyte to cross the blood vessel wall
by squeezing between the endothelial cells.
Second, the chemokines direct the migration of the leukocyte along a gradient of the chemokine
that increases in concentration toward the site of infection. This is achieved by the binding of the
small, soluble chemokines to proteoglycan molecules in the extracellular matrix and on endothelial

4. cell surfaces, thus displaying the chemokines on a solid substrate along which the leukocytes can
migrate.
Vasoactive mediators
Chemokines do not act alone in cell recruitment, which also requires the action of vasoactive
mediators to bring leukocytes close to the blood vessel endothelium and cytokines such as TNF-α
to induce the necessary adhesion molecules on the endothelial cells [4, 5]
Cell-adhesion molecules:
During inflammatory response, certain molecules called cell-adhesion molecules are induced on
the surface of local blood vessels endothelium, which act as a mediator in the recruitment of
activated phagocytes to site of infection. This recruitment is one of the most important function of
innate immunity.
Families of cell-adhesion molecules:
The adhesion molecules are grouped according to their molecular structure. Adhesion molecules
are grouped into three families which are important for leukocyte recruitment. They play a part in
leukocyte migration,directing many aspects of tissue and organ development, homing, and cell cell
interactions: the selectins, the integrins, and proteins of the immunoglobulin superfamily.
1.Selectins: Membrane glycoproteins with a distal lectinlike domain that binds specific
carbohydrate groups.Members of this family are induced on activated endothelium and initiate
endothelial leukocyte interactions by binding to fucosylated oligosaccharide ligands on passing
leukocytes. The three family members are E-selectin (endothelial), L-selectin (leukocyte), and P-
selectin (platelet).
2.Integrin: Phagocyte adhesion to vascular endothelium is mediated by integrins . Two of the
leukocyte integrins that function as complement receptors are CR3 and CR4.
3.immnologlobulin superfamily:
Various roles in cell adhesion. They are the ligands for integrins. Vascular endothelium, when it
is activated by inflammatory mediators, expresses two adhesion molecules ICAM-1 and ICAM-2.

5. These are ligands for integrins. The leukocyte integrins important for extravasation are LFA-1 and
Mac-1 [6, 7]
Extravasation:
Under normal conditions, leukocytes flow is faster and are restricted to center of blood vessels but
monocytes may migrate continuously into the tissues, where they differentiate into macrophage.
During the inflammatory response, the induction of adhesion molecules on the endothelial cells,
as well as induced changes in the adhesion molecules expressed on leukocytes, recruit large
numbers of circulating leukocytes, initially neutrophils and later monocytes, into the site of an
infection. The local blood vessels also dilate (slowing blood flow) which allow the leukocytes
movement towards endothelium cells.The migration of leukocytes out of blood vessels, a process
known as extravasation, is thought to occur in four steps.
Step 1 (Rolling adhesion) :
The first step involves family of selectins. The activation of endothelium is driven by interactions
with macrophage cytokines, particularly TNF-α, which induces rapid externalization of granules
(Weibel Palade bodies) containing P-selectin. After the appearance of P-selectin on the cell
surface, E-selectin is synthesized and both these proteins then interact with sulfatedsialyl-Lewisx,
which is present on the surface of neutrophils. This interaction cannot anchor the cells against the
shearing force of the flow of blood, and instead they roll along the endothelium, continually
making and breaking contact
Step 2 (Tight binding):
This second step depends upon interactions between the circulating monocytes and
polymorphonuclear leukocyte integrins LFA-1 and Mac-1 (which required for extravasation, and
for migration toward chemoattractants) with molecules on endothelium such as ICAM-1, which
is also induced on endothelial cells by TNF-α. LFA-1 and Mac-1 normally adhere only weakly,
but IL-8 or other chemokines, bound to proteoglycans on the surface of endothelial cells, trigger a
conformational change in LFA-1 and Mac-1 on the rolling leukocyte, which greatly increases its
adhesive properties. In consequence, the leukocyte attaches firmly to the endothelium and rolling
is arrested.

6. Step 3 (Diapedesis):
This step involve LFA-1 and Mac1, as well as a further adhesive interaction involving an
immunoglobulin-related molecule called PECAM or CD31 that are expressed both on leukocyte
and at the intercellular junctions of endothelial cells. Tight binding of these molecules arrests the
rolling and allows the leukocyte to squeeze between the endothelial cells.
It then penetrates the basement membrane (an extracellular matrix structure) with the aid of
proteolytic enzymes that break down the proteins of the basement membrane. The movement
through the vessel wall is known as diapedesis, and enables phagocytes to enter the subepithelial
tissues.
Step 4 (migration):
The fourth and final step in extravasation is the migration of leukocytes through the tissues under
the influence of chemokine. Chemokines such as IL-8 are produced at the site of infection and
bind to proteoglycans in the extracellular matrix. They form a matrix-associated concentration
gradient along which the leukocyte can migrate to the focus of infection. Neutrophils make up the
first wave of cells that cross the blood vessel wall to enter inflammatory sites while onocytes can
be recruited later [8-10].
Tumor necrosis factor-α (cytokine):
To prevent pathogen from entering into tissues or organs from blood, one of the role of
inflammatory mediators is to express protein on surface of endothelial cells that starts blood
clotting and thus blocking blood vessel by cutting off blood flow. In the early stage the lymph that
leaks out in tissue carries pathogen that is enclosed in phagocytic cell, especially dendritic cells,
and take to lymph node where adaptive immune response can be initiated.
Importance of TNF-α in control of local infection:
The importance of TNF-α is that it controls and respond to infection at localized area. It was
determined by experiments in which rabbits are infected locally with a bacterium. Normally, the
infection will be control at the site of the infection; if, however, an injection of anti-TNF-α

7. antibody is also given to block the action of TNF-α, the infection spreads via the blood to other
organs.
Release of TNF-α systematically:
Once an infection spreads to the bloodstream, however, the TNF-α which works so effectively in
local infection become catastrophic if release systematically.
Sepsis:
The presence of infection in the bloodstream which is complemented by the release of TNF-α by
macrophages in the lymphatic organs (liver, spleen, and other sites).
Causes of TNF-α f release systematically:
 Vasodilation
 Increased vascular permeability
This will results in septic shock, which triggers dispersed intravascular coagulation (blood
clotting) leading to the generation of clots in many small vessels and the massive consumption of
clotting proteins, which results in inability of patient to clot blood.
Consequences:
 Fail to clot blood
 Failure of vital organs (kidneys, liver, heart, and lungs)
 Failure of normal perfusion of blood
 Death occur
Mutant TNF-α receptor gene:
If mutation in TNF-α receptor gene the individual become resistant to septic shock but at a same
time don’t able to control infection at local area. Although the features of TNF-α that make it so
valuable in containing local infection are precisely those that give it a central role in the
pathogenesis of septic shock, it is clear from the evolutionary conservation of TNF-α that its

8. benefits in the former area far offset the overwhelming consequences of its systemic release [11-
14].
Cytokines released by phagocytes activate the acute-phase response.
The cytokines produced by macrophages has long-range effects. One of them is the elevation of
body temperature, which is mainly caused by TNF-α, IL- 1, and IL-6. These are termed
endogenous pyrogens because they cause fever and derive from an endogenous source rather than
from bacterial components. Fever is generally beneficial to host defense; most pathogens grow
better at lower temperatures and adaptive immune responses are more intense at elevated
temperatures. Host cells are also protected from the deleterious effects of TNF-α at raised
temperatures.
Acute-phase response:
This involves a shift in the proteins secreted by the liver into the blood plasma and results from
the action of IL-1, IL-6, and TNF-α on hepatocytes. In the acute-phase response, levels of some
plasma proteins go down, while levels of others increase markedly. The proteins whose synthesis
is induced by TNF-α, IL-1, and IL-6 are called acute-phase proteins. They mimic the action of
antibodies, but, unlike antibodies, these proteins have broad specificity for pathogen-associated
molecular patterns and depend only on the presence of cytokines for their production.
Examples: C-reactive protein and Mannan-binding lectin [15-18]
Interferons:
Infection of cells with viruses induces the production of proteins that are known as interferons
because they were found to interfere with viral replication in previously uninfected tissue culture
cells. They are believed to have a similar role in vivo, blocking the spread of viruses to uninfected
cells. These antiviral effector molecules, called interferon-α (IFN-α) and interferon-β (IFN-β).
Defense Contribution by interferons:
Interferons make several contributions to defense against viral infection. An obvious and important
effect is the induction of a state of resistance to viral replication in all cells. . IFN-α and IFN-β are
secreted by the infected cell and then bind to a common cell-surface receptor, known as the

9. interferon receptor, on both the infected cell and nearby cells. This signaling pathway, which we
will describe in detail in Chapter 6, rapidly induces new gene transcription as the Janus-family
kinases directly phosphorylate signal-transducing activators of transcription known as STATs,
which translocate to the nucleus where they activate the transcription of several different genes. In
this way interferon induces the synthesis of several host cell proteins that contribute to the
inhibition of viral replication.
Functions of interferons:(IFN)-α and –β)
The interferons (IFN)-α and -β have three major functions:
1. They induce resistance to viral replication in uninfected cells by activating genes that cause
the destruction of mRNA and inhibit the translation of viral and some host proteins
2. They can induce MHC class I expression in most cell types in the body, thus enhancing
their resistance to NK cells
3. They activate NK cells, which then kill virus-infected cells selectively [19-23].
Natural killer cells and interferons; acting as early defense:
Natural killer cells (NK cells) develop in the bone marrow from the common lymphoid progenitor
cell and circulate in the blood. They are larger than T and B lymphocytes, have distinctive
cytoplasmic granules, and are functionally identified by their ability to kill certain lymphoid tumor
cell lines in vitro without the need for prior immunization or activation
Mechanism of killing:
The mechanism of NK cell killing is the same as that used by the cytotoxic T cells generated in an
adaptive immune response; cytotoxic granules are released onto the surface of the bound target
cell, and the effector proteins they contain penetrate the cell membrane and induce programmed
cell death
Activation by interferons:
NK cells are activated in response to interferons or macrophage-derived cytokines. Although NK
cells that can kill sensitive targets can be isolated from uninfected individuals, this activity is
increased by between twentyfold and one hundredfold when NK cells are exposed to IFN-α and

10. IFN-β or to the NK cell-activating factor IL-12, which is one of the cytokines produced early in
many infections.
IL-12, in synergy with TNF-α, can also elicit the production of large amounts of IFN-γ by NK
cells, and this secreted IFN-γ is crucial in controlling some infections before T cells have been
activated to produce this cytokine [24-26].
NK Cells
NK cells possess receptors for self-molecules that inhibit their activation against uninfected host
cells. If NK cells are to mediate host defense against infection with viruses and other pathogens,
they must have some mechanism for distinguishing infected from uninfected cells. For this process
recognition of “altered self” is involved.
NK cells surface receptor
NK cells have two types of surface receptor that control their cytotoxic activity.
1. One type is an 'activating receptor:' it triggers killing by the NK cell. Several types of
receptor
Provide this activation signal, including calcium-binding C-type lectins that recognize a wide
variety of carbohydrate ligands present on many cells.
2. A second set of receptors inhibit activation, and prevent NK cells from killing normal
Host cells. These 'inhibitory receptors' are specific for MHC class I alleles, which helps to explain
why NK cells selectively kill target cells bearing low levels of MHC class I molecules.
Methods of recognition by NK cells
1. Thus, one possible mechanism by which NK cells distinguish infected from uninfected
cells is by recognizing alterations in MHC class I expression (Fig. 2.42).
2. Another is that they recognize changes in cell-surface glycoproteins induced by viral or
bacterial infection.
Mechanism

11. A proposed mechanism of recognition is shown. NK cells can use several different receptors that
signal them to kill, including Lectin like activating receptors, or 'killer receptors,' that recognize
carbohydrate on self-cells. However, another set of receptors, killer inhibitory receptors (KIRs) in
the human, recognize MHC class I molecules and inhibit killing by NK cells by overruling the
actions of the killer receptors. This inhibitory signal is lost when cells do not express MHC class
I and perhaps also in cells infected with virus, which might inhibit MHC class I expression or alter
its conformation. In contrast, infected cells can fail to increase MHC class I expression, making
them targets for activated NK cells.
.Inhibitory NK receptors
. In humans, there are inhibitory receptors that recognize distinct HLA-B and HLA-C alleles (these
are MHC class I alleles encoded by the B and C loci of the human MHC or Human Leukocyte
Antigen gene complex). Being members of the immunoglobulin gene superfamily; they are usually
called p58 and p70, or killer inhibitory receptors (KIRs). In
Addition, human NK cells express a heterodimer of two C-type lectins, called CD94 and NKG2.
Other inhibitory NK receptors specific for the products of the MHC class I loci are rapidly being
defined, and all are members of either the immunoglobulin-like KIR family or the Ly49-
Like C-type lectins.
Mechanism of inhibitory receptors
Signaling by the inhibitory NK receptors suppresses the killing activity of NK cells. This means
that NK cells will not kill healthy genetically identical cells with normal expression of MHC class
I molecules, such as the other cells of the body. Virus-infected cells, however, can become
susceptible to killing by NK cells by a variety of mechanisms.
1. Inhibition of protein synthesis
First, some viruses inhibit all protein synthesis in their host cells, so synthesis of MHC class I
proteins would be blocked in infected cells, even while being augmented by interferon in
uninfected cells. The reduced level of MHC class I expression in infected cells would make them

12. correspondingly less able to inhibit NK cells through their MHC-specific receptors, and therefore
more susceptible to killing.
2. Prevention of export of MHC
Second, some viruses can selectively prevent the export of MHC class I molecules, which might
allow the infected cell to evade recognition by the cytotoxic T cells of the adaptive immune
response but would make it susceptible to killing by NK cells. Finally virus infection alters the
glycosylation of cellular proteins, perhaps allowing recognition by activating receptors to
dominate or removing the normal ligand for the inhibitory receptors. Either of these last two
mechanisms could allow infected cells to be detected even when the level of MHC class I
expression had not been altered [27-29].
Summary:
Innate immunity can use a variety of induced effector mechanisms to clear an infection or, failing
that, to hold it in check until the pathogen can be recognized by the adaptive immune system.
These effector mechanisms are all regulated by germ line-encoded receptor systems that are able
to discriminate between no infected self and infectious non self-ligands. Thus the phagocytes'
ability to discriminate between self and pathogen controls its release of pro inflammatory
chemokines and cytokines that act together to recruit more phagocytic cells, especially neutrophils,
which can also recognize pathogens, to the site of infection. Furthermore, cytokines released by
tissue phagocytic cells induce fever, the production of acute-phase response proteins including the
pathogen-binding mannan-bindinglectin and the C-reactive proteins, and the mobilization of
antigen-presenting cells that induce the adaptive immune response. Viral pathogens are recognized
by the cells in which they replicate, leading to the production of interferon that serves to inhibit
viral replication and to activate NK cells, which in turn can distinguish infected from non-infected
cells.
References
1. Janeway, C.A., et al., Immunobiology: the immune system in health and disease. 2005.
2. Larsson, B.-M., et al., Gram positive bacteria induce IL-6 and IL-8 production in human alveolar
macrophages and epithelial cells. Inflammation, 1999. 23(3): p. 217-230.

13. 3. Svanborg, C., G. Godaly, and M. Hedlund, Cytokine responses during mucosal infections: role in
disease pathogenesis and host defence. Current opinion in microbiology, 1999. 2(1): p. 99-103.
4. DeVries, M.E., et al., Defining the origins and evolution of the chemokine/chemokine receptor
system. The Journal of Immunology, 2006. 176(1): p. 401-415.
5. Scapini,P.,etal., Theneutrophilasa cellular sourceof chemokines. Immunologicalreviews,2000.
177(1): p. 195-203.
6. Jagels,M.A.,P.J.Daffern,and T.E.Hugli,C3a and C5a enhancegranulocyteadhesion to endothelial
and epithelial cell monolayers: epithelial and endothelial priming is required for C3a-induced
eosinophil adhesion. Immunopharmacology, 2000. 46(3): p. 209-222.
7. Muller, W.A. and G.J. Randolph, Migration of leukocytes across endothelium and beyond:
molecules involved in the transmigration and fate of monocytes. Journal of leukocyte biology,
1999. 66(5): p. 698-704.
8. Frenette, P. and D. Wagner, Insights into selectin function from knockout mice. Thrombosis and
haemostasis, 1997. 78(1): p. 60-64.
9. Knott,P.G., etal., Rapid up-regulation of CXCchemokinesin the airwaysafterAg-specific CD4+ T
cell activation. The Journal of Immunology, 2001. 166(2): p. 1233-1240.
10. Muruve,D.A.,etal., Adenoviralgenetherapy leadsto rapid induction of multiplechemokinesand
acuteneutrophil-dependenthepaticinjury in vivo. Human gene therapy, 1999. 10(6): p. 965-976.
11. Hultgren, O., et al., TNF/lymphotoxin-α double-mutant mice resist septic arthritis but display
increased mortality in response to Staphylococcus aureus. The Journal of Immunology, 1998.
161(11): p. 5937-5942.
12. Krishnaswamy,G.,etal., Human endotheliumasa sourceof multifunctionalcytokines:molecular
regulation and possible role in human disease. Journal of interferon & cytokine research, 1999.
19(2): p. 91-104.
13. Rigato, O., et al., Tumor necrosis factor alpha (TNF-α) and sepsis: evidence for a role in host
defense. Infection, 1996. 24(4): p. 314-318.
14. Sriskandan, S. and J. Cohen, Gram-positive sepsis: mechanisms and differences from gram-
negative sepsis. Infectious disease clinics of North America, 1999. 13(2): p. 397-412.
15. Bopst, M., et al., The combined inactivation of tumor necrosis factor and interleukin‐6 prevents
induction of themajoracutephaseproteinsby endotoxin. Europeanjournalof immunology,1998.
28(12): p. 4130-4137.

14. 16. Horn, F., C. Henze, and K. Heidrich, Interleukin-6 signal transduction and lymphocyte function.
Immunobiology, 2000. 202(2): p. 151-167.
17. Ramadori, G. and B. Christ. Cytokines and the hepatic acute-phase response. in Seminars in liver
disease. 1998.
18. Uhlar, C.M. and A.S. Whitehead, Serum amyloid A, the major vertebrate acute‐phase reactant.
European Journal of Biochemistry, 1999. 265(2): p. 501-523.
19. Balachandran, S., et al., Essential role for the dsRNA-dependent protein kinase PKR in innate
immunity to viral infection. Immunity, 2000. 13(1): p. 129-141.
20. Bogdan, C., The function of type I interferons in antimicrobial immunity. Current opinion in
immunology, 2000. 12(4): p. 419-424.
21. Durbin, J.E., et al., Type I IFN modulates innate and specific antiviral immunity. The Journal of
Immunology, 2000. 164(8): p. 4220-4228.
22. Hayward, A.R., K. Chmura, and M. Cosyns, Interferon-γ is required for innate immunity to
Cryptosporidium parvum in mice. Journal of Infectious Diseases, 2000. 182(3): p. 1001-1004.
23. Kadowaki, N., et al., Natural interferon α/β–producing cells link innate and adaptive immunity.
The Journal of experimental medicine, 2000. 192(2): p. 219-226.
24. Biron, C.A., et al., Natural killer cells in antiviral defense: function and regulation by innate
cytokines. Annual review of immunology, 1999. 17(1): p. 189-220.
25. Carnaud,C., et al., Cutting edge: cross-talkbetween cells of the innate immunesystem:NKT cells
rapidly activate NK cells. The Journal of Immunology, 1999. 163(9): p. 4647-4650.
26. Salazar-Mather, T.P., T.A. Hamilton, and C.A. Biron, A chemokine-to-cytokine-to-chemokine
cascadecritical in antiviral defense. The Journal of clinicalinvestigation, 2000. 105(7): p. 985-993.
27. Lanier, L.L., NK cell receptors. Annual review of immunology, 1998. 16(1): p. 359-393.
28. Renard, V., et al., Transduction of cytotoxic signals in natural killer cells: a general model of fine
tuning between activatory andinhibitory pathwaysin lymphocytes. Immunological reviews,1997.
155(1): p. 205-221.
29. Valés-Gómez,M.,H. Reyburn,andJ. Strominger, Molecularanalysesof the interactionsbetween
human NK receptors and their HLA ligands. Human immunology, 2000. 61(1): p. 28-38.