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natural killer ( nk ) cells are regulated in part by inhibitory receptors that recognize mhc class i molecules on normal cells . in humans , inhibitory receptors that recognize classical mhc class i molecules ( hla -
a , hla - b , and hla - c ) belong to the kir family .
kirs are a family of 15 closely linked genes located on chromosome 19q13.4 , which encode both inhibitory and activating receptors that are expressed by nk cells and by subsets of  t cells and memory and effector  t cells .
the reason for kir diversity and the contribution of individual kirs to signaling in nk cells and t cells are not fully understood , but their importance has been underscored by several recent genetic studies , including one in this issue ( 1 ) , which have linked combinations of kir and hla genes with the outcome of various diseases ( table i ) ( 28 ) .
associations with different hla  kir combinations , involving activating kirs or inhibitory kirs to different extents , have been described .
the data suggest that disease can be modified by specific kir  ligand interactions , rather than by global responsiveness of nk cells or t cells .
disease associations with combinations of kir and hla genes kirs contain either two or three immunoglobulin - like domains with either long ( 2dl , 3dl ) or short ( 2ds , 3ds ) cytoplasmic tails ( table ii ) ( 9 ) .
long - tailed receptors carry one or two immunoreceptor tyrosine - based inhibition motifs ( itims ) , which contribute to inhibitory signaling .
short - tailed receptors have a lysine residue in their transmembrane domain that is required for pairing with the immunoreceptor tyrosine - based activation motif ( itam)containing adaptor dap12 .
several inhibitory kirs have well - defined mhc class i ligands ( table ii ) ( 10 , 11 ) .
the ligands for activating kirs , however , have been more elusive . despite high sequence similarity with some of the inhibitory receptors , activating kirs
kir molecules and their hla ligands , extracellular immunoglobulin domain ; , transmembrane charge ; , cytoplasmic itim .
a striking feature of kir genes is their lack of conservation among species and their rapid evolution , which can not be accounted for solely by divergence in hla class i molecules ( 15 ) .
if kir gene evolution were pathogen driven , some of the diversity would be expected to correlate with resistance or sensitivity to certain infectious diseases .
indeed , several genetic studies of viral infection have revealed an influence of hla  kir gene interactions on disease outcome ( table i ) .
an interaction between kir3ds1 and a subset of hla - bw4 alleles  those with ile at position 80is associated with delayed progression to aids in hiv - infected individuals ( 2 ) . in the case of hepatitis c virus ( hcv ) infection , homozygosity of both hla - c1 and kir2dl3
the latter finding is that kir2dl3 binds hla - c with lower affinity than kir2dl1 and kir2dl2 receptors , thus reducing nk cell inhibition and favoring resolution of the infection .
however , direct affinity measurements have not revealed a difference between kir2dl binding to their respective hla - c ligands ( table ii ) .
the report in this issue ( 1 ) reveals a predisposition to human papilloma virus ( hpv)induced cervical cancer with hla  kir gene combinations that seem to favor nk cell activation .
in contrast to correlations seen with hiv and hcv infections , disease progression toward cervical neoplasia seems enhanced by an increase in activation signals .
thus , a combination of kir2ds1 and/or kir2ds2 coupled with homozygosity of an hla - c group favors susceptibility to psoriatic arthritis ( 5 ) .
susceptibility could be due to reduced nk cell inhibition , as individuals homozygous for hla - c1 lack a ligand for kir2dl2 and kir2dl3 , and those homozygous for hla - c2 lack a ligand for kir2dl1 .
similarly , kir2ds2 combined with hla - c1 in the absence of hla - c2 and hla - bw4 is associated with increased susceptibility to type i diabetes ( 3 ) . likewise ,
kir2ds1 in combination with hla - cw*06 is a risk factor for psoriasis vulgaris ( 7 ) .
kir combinations that favor nk cell or t cell activation may have been selected to improve resistance to viruses and to malignancy ( 8) , despite an associated risk of developing autoimmunity ( table i ) .
kir gene combinations that seem to favor nk cell inhibition have also been associated with preeclampsia ( 6 ) , a potentially fatal condition caused by incomplete remodeling of spiral arteries in maternal decidua and by high blood pressure during pregnancy .
susceptibility is associated with the combination of hla - c2 on fetal trophoblast cells and kir2dl1 on maternal cells , and is further increased by the absence of activating kir2ds genes ( 6 ) .
a potential explanation of these findings is that kir2dl1 confers a strong inhibition , compared with kir2dl2 or kir2dl3 , which prevents activation of nk cells during interaction with fetal trophoblast cells in the decidua . in this context ,
interactions with dendritic cells , macrophages , and fetal trophoblast cells can regulate nk cell activity by influencing cytokine production , cytotoxicity , and stimulation of t helper-1 responses .
stimulation of nk cells can be beneficial during virus infections , malignant transformation , and pregnancy , but deleterious in the context of autoimmunity or neoplastic transformation .
the latter may be provoked by chronic inflammation , which is a known risk factor in developing cancer during persistent infections .
hpv establishes latency by preventing nk - mediated lysis of infected cells ( 16 ) .
it would be interesting to test if hpv infection provokes a proinflammatory cytokine response from nk cells in the absence of cytotoxicity , thereby favoring neoplasia .
a simple interpretation of the observed genetic correlations might suggest that kir3ds1 stimulates cytokine production by nk cells , which contributes to inflammation .
however , a few key aspects of nk cell biology need to be considered when interpreting such genetic analyses .
understanding the basis for the observed genetic associations is complicated by the large repertoire of receptors used by nk cells to interpret their environment .
there is extensive polymorphism among kir haplotypes , which differ not only in nucleotide sequence but also in gene content ( 17 ) .
different haplotypes carry different numbers of kir genes , some with few or no activating kirs ( a haplotypes ) and others with several activating kirs ( b haplotypes ) .
individuals with several activating kir genes simply have a higher probability of expressing activating kirs on any given nk cell than individuals who have fewer activating kirs .
therefore , a given disease association with hla  kir gene combinations , for instance , an activating kir and its hla ligand , can not be interpreted simply as an overall enhancement in nk cell activation signals .
furthermore , a selection process ( the mechanism of which is unknown ) is in place to ensure that each nk cell has at least one inhibitory receptor specific for a self hla class i molecule .
if , for instance , an nk cell lacks all of the major inhibitory kirs , it will express the heterodimeric inhibitory receptor cd94nkg2a ( 18 ) , which binds to the nonclassical hla - e . a new inhibitory receptor 
ligand combination , which is independent of mhc class i , has recently been discovered on mouse nk cells : binding of nkr - p1 receptors to the widely expressed c - type lectin clr - b inhibits nk cell activation ( 19 , 20 ) .
therefore , it is not clear that kir haplotypes carrying several activating kirs would necessarily result in nk cells that are more easily activated , as the expression of activating kirs should be compensated by the expression of inhibitory receptors .
activating kirs are completely dispensable , as kir haplotypes lacking all functional 2ds and 3ds genes are common ( 21 ) . in addition , all individuals have a subset of nk cells that are completely devoid of activating kirs . as activating and inhibitory kirs
are not coordinately expressed , it is unlikely that activating kirs contribute to the function of inhibitory kirs .
the ligand specificity of activating kirs is unclear . kir2ds1 and kir2ds2 may bind hla - c with a lower affinity than that of closely related inhibitory kirs ( 12 , 14 ) , but it is also possible that alternate ligands exist , such as the non - hla ligand for kir2ds4 on melanoma cells ( 22 ) . in the mouse ly49 receptor family , which is structurally distinct from but functionally equivalent to human kirs , the activating ly49h and the inhibitory ly49i receptors bind to the m157 protein of mouse cytomegalovirus ( 23 , 24 ) , suggesting that kirs may also have viral protein ligands .
it is essential to determine the ligand specificity of activating kirs in order to interpret genetic correlations with diseases .
expression of activating kirs on subsets of t cells could contribute to some of the associations seen in the genetic studies .
it is conceivable that activating kirs may synergize with tcr - mediated signals to cause aberrant immune activation and autoimmune reactions .
kir2ds2 , which is expressed by a large percentage of cd4cd28 t cells in rheumatoid arthritis patients with vascular complications , is also a genetic risk factor for this disease ( 25 ) .
even though t cells lack dap12 , expression of kir2ds2 costimulated tcr signals which , although suboptimal , resulted in cytokine secretion ( 26 ) .
side chains that extend out of the peptide - binding groove of hla - b and hla - c molecules can interfere with binding of inhibitory kirs ( 10 ) .
although peptide - specific recognition by activating kirs has been proposed as a potential mechanism to activate nk cells during infections , it is extremely unlikely that self / nonself discrimination is achieved by kirs , primarily because each kir binds to different hla - b or hla - c molecules , each of which has its own rules for peptide binding .
therefore , recognition by kir can only work if the peptide does not contribute to specificity .
the extensive polymorphism of hla class i and the very limited repertoire of kir are not compatible with peptide - specific binding to hla class i in the context of diseases or infections .
in contrast , cd94 binding to the nonpolymorphic hla - e is governed by peptide specificity ( 9 ) .
hla - e normally binds a peptide derived from signal sequences of other hla class i molecules , and recognition by cd94 is lost when hla - e instead binds a peptide derived from the signal sequence of heat shock protein 60 ( 27 ) .
situation could induce the killing of cells undergoing a stress response by nk cells that are normally inhibited by hla - e .
several of the genetic studies have suggested a model whereby inhibition of nk cells by some kir  hla combinations is stronger than others . in this model ,
the inhibition by kir2dl1hla - c2 is strongest , followed by kir2dl2hla - c1 , and finally kir2dl3hla - c1 ( 1 , 46 , 17 ) .
accordingly , weaker inhibitory interactions result in greater nk cell activation and better protection from virus infection , or greater susceptibility to autoimmunity .
similarly , in preeclampsia too strong an inhibition by kir2dl1hla - c2 interactions prevents proper nk cell activation ( 6 ) , which may be required to stimulate vascularization .
( 1 ) also support such a connection between strength of kir - mediated inhibition and disease outcome .
however , careful affinity measurements by surface plasmon resonance with each of the purified kir2dl molecules and their hla - c ligands have resulted in almost identical values ( table ii ) . on the other hand , binding of kir2dl  fc fusion proteins to hla - c followed a pattern consistent with diminishing strength , in the order kir2dl1>kir2dl2>kir2dl3 ( 13 ) .
differences in inhibitory strength among kir2dls may also be related to signaling in the cytosol , and not to hla - c binding .
an interesting feature of kir2dls is a requirement for zn in their inhibitory function ( 28 ) .
kinetic measurements of kir2dl binding to hla - c revealed slower off rates in the presence of zn , particularly in the case of kir2dl1 ( 14 ) .
thus , it is possible that differences in sustained engagement of kir due to zn could translate into differences in strength of inhibition .
an analysis of receptor  ligand interactions in the context of diseases is required to understand how hla 
kir genotypes contribute to disease . it will be important to determine in what tissue and with what ligand - expressing cells are kir - expressing nk cells and t cells interacting .
such questions are difficult to address , as the lack of kir conservation in mice precludes the use of a convenient animal model .
a major effort is underway to type kir gene polymorphism and expression in the context of kir - mismatched bone marrow transplantation ( 17 ) .
will a precise analysis of kir alleles and kir expression , rather than overall genotypes , result in stronger associations or loss of statistical significance ?
it is also possible that the strong linkage disequilibrium within the kir gene complex accounts for disease associations , and that a linked gene is responsible for the observed effect .
disease associations were first reported in the 1970s ( 29 ) , a decade before the realization that hla molecules bind peptides , and two decades before the resolution of tcr  mhc structures .
hopefully a molecular basis for the new disease associations with hla  kir gene combinations will be provided before the year 2025 .
combinations of hla and killer cell immunoglobulin  like receptor ( kir ) genes have been associated with diseases as diverse as autoimmunity , viral infections , reproductive failure , and now cancer . 
 much as early observations of disease associations with hla polymorphism preceded a detailed knowledge of hla recognition by t cell receptors , the recently reported disease associations with hla  
 kir gene combinations beg for a better understanding of the underlying mechanisms .