Killer cell immunoglobulin (Ig)-like receptors (KIR), also called killer cell inhibitory receptors, are glycoproteins expressed in natural killer (NK) cells and some T cells. The KIR family is estimated to include about 11 genes. Some members of the KIR family bind specifically to certain HLA class I allotypes. Ligation of such KIR by HLA class I molecules on target cells results in inhibition of the NK or T cell cytotoxic activity. The KIR family is subdivided into two subfamilies based on structure. Some KIR members have two Ig domains (KIR2D), others have three Ig domains (KIR3D). KIR members vary also in the length of the cytoplasmic tails. Typically, KIR with a long cytoplasmic tail (L) deliver an inhibitory signal, whereas KIR with a short cytoplasmic tail (S) can activate NK or T cell responses

The nomenclature used in these KIR documents was devised by a group of experts and it is operationally very useful, but does not represent the consensus of an international commitee**


• KIR Family Tree
• The KIR family is subdivided into two subfamilies based on structure: KIR2D and KIR3D, with further subdivision into forms with Short and Long intracytoplasmic tails
• The first and second Ig domains in KIR2D are closely related in amino acid sequence to the second and third Ig domains in KIR3D. These two related Ig domains are called D1 and D2, respectively. D0 is the first Ig domain in KIR3D
• Most of the long cytoplasmic tails carry two immunoreceptor tyrosine-based inhibition motifs (ITIM)
• The short cytoplasmic tails are truncated before the first ITIM and are connected to a transmembrane region which includes a lysine residue
• Diagram of the KIR family members
  
Click on image for larger view

• KIR2DL, also called p58 (Moretta et al. 1993), has two Ig domains (D1 and D2) and cytoplasmic tails of 76-84 amino acids (Wagtmann et al. 1995a; Colonna and Samaridis 1995). The KIR2DL4 member has a D0-D2 domain configuration, and a cytoplasmic tail of 114 amino acids(Selvakumar et al. 1997b)
• Its members include: KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4

• KIR2DS, also called p50 (Moretta et al. 1995), have two Ig domains and a cytoplasmic tail of 39 amino acids (Wagtmann et al. 1995a; Colonna and Samaridis 1995; Biassoni et al. 1996)
• Its members include: KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5

• KIR3DL, also called p70 and p140 (Litwin et al. 1994; Pende et al. 1996), have three Ig domains (D0, D1, and D2) and cytoplasmic tails of 84-95 amino acids (Colonna and Samaridis 1995; D'Andrea et al. 1995; Wagtmann et al. 1995b; Pende et al. 1996)
• Its members include: KIR3DL1 and KIR3DL2

• KIR3DS have three Ig domains and a cytoplasmic tail of 27 amino acids (Dohring et al. 1996a)
• Its one member is: KIR3DS1

• Diagram of the KIR amino acid sequence alignment

• None

• None

• KIR with ITIM sequences in the cytoplasmic domain (KIR2DL and KIR3DL) inhibit NK and CTL-mediated lysis against certain target cells expressing an appropriate MHC class I ligand. In addition, interactions between KIR on NK or T cells and MHC class I on antigen-presenting cells can inhibit cytokine production (D'Andrea et al. 1996)
• In contrast, T or NK cells expressing KIR without an ITIM (eg. KIR2DS) may enhance cytolysis against target cells expressing an appropriate MHC class I ligand (Moretta et al. 1995; Mandelboim et al. 1996)
• However, inhibitory KIR can prevent stimulation via an activating KIR if the potential target or antigen presenting cell also expresses a ligand of the inhibitory KIR (Moretta et al. 1995)

• Most NK and some T cells express KIR (Mingari et al. 1996**)
• Expression of KIR in individual NK cells is complex; NK cells may express several members of the KIR family* (Wagtmann et al. 1995a; Valiante et al. 1997)
• The repertoire of KIR molecules varies among NK cells and is not determined solely by the HLA haplotypes of the host (Gumperz et al. 1996; Valiante et al. 1997)

• In murine models, inhibitory NK cell receptors that are functional homologs of human KIR (eg. the Ly49 receptors) regulate rejection of bone marrow grafts from semi-allogeneic or allogeneic donors (George et al. 1997)
• Expression of a human KIR transgene controls NK-mediated rejection of allogeneic bone marrow grafts (Cambiaggi et al. 1997)**
• There is also evidence that KIR may be expressed on melanoma-specific CTL and regulate their ability to kill these tumors (Ikeda et al. 1997)

• Extracellular region: two (D1-D2) or three (D0-D1-D2) Ig domains precede a proline-serine-rich stem of 17 amino acids that links the Ig domain D2 to the transmembrane region
• The crystal structure of the D1 and D2 domains of a KIR2D reveals a similarity with the structure of the hematopoietic receptor family (Fan et al. 1997)

• The KIR family is encoded by genes on chromosome 19, at cytogenetic band q13.4 (Baker et al. 1995)
• The KIR gene complex is telomeric to the ILT/MIR/LIR gene family and centromeric to the gene for the Fc alpha receptor (Fc alphaR) (Wagtmann et al. 1997)
• The exons of the genes for KIR2DL3 and KIR2DL4 have been sequenced (Wilson et al. 1997; Selvakumar et al. 1997b) (GenBank AF003116-AF003123, U97173-U97180).

• KIR2D bind zinc (Rajagopalan et al. 1995)
• There is no mouse counterpart of KIR
• Proteins that share 40% amino acid sequence identity with any one of the KIR Ig domains include:
  • human ILT/MIR/LIR (Samaridis and Colonna 1997; Wagtmann et al. 1997, Cosman et al. 1997
    • ILT2 functions as an inhibitory receptor for HLA class I utilized by NK and CTL subsets (Colonna et al. 1997)**
  • LAIR (Meyaard et al. 1997),
  • Fc alphaR (Maliszewski et al. 1990)
  • mouse gp49 (Castells et al. 1994)
  • p91/PIR (Hayami et al. 1997; Kubagawa et al. 1997)
• Inhibition of human NK cells is also achieved by the CD94/NKG2 family of receptors that are specific for HLA-E (Braud et al. 1998; Borrego et al. 1998; Lee et al. 1998). In contrast to KIR, these receptors are disulfide-linked heterodimers of C-type lectin-like molecules

REVIEWS

Lanier LL. NK cell receptors. Annu. Rev. Immunol. 1998 16:359 PubMed

Moretta A, Bottino C, Vitale M, Pende D, Biassoni R, Mingari MC and Moretta L. Receptors for HLA class-I molecules in human natural killer cells. Annu. Rev. Immunol. 1996 14:619 PubMed

Parham, P.(Ed) (1997). NK cells, MHC class I antigens and missing self. Immunol. Rev. 155, 5-221

PRIMARY CITATIONS

Baker, E., D'Andrea, A., Phillips, J.H., Sutherland, G.R., and Lanier, L.L. (1995). Natural killer cell receptor for HLA-B allotypes, NKB1: map position 19q13.4. Chromosome Res. 3, 511

Biassoni R, Cantoni C, Falco M, Verdiani S, Bottino C, Vitale M, Conte R, Poggi A, Moretta A and Moretta L. The human leukocyte antigen (HLA)-C-specific 'activatory' or 'inhibitory' natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions. J. Exp. Med. 1996 183:645 PubMed

Biassoni R, Pessino A, Malaspina A, Cantoni C, Bottino C, Sivori S, Moretta L and Moretta A. Role of amino acid position 70 in the binding affinity of p50.1 and p58.1 receptors for HLA-Cw4 molecules. Eur. J. Immunol. 1997 27:3095 PubMed

Borrego F, Ulbrecht M, Weiss EH, Coligan JE and Brooks AG. Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J. Exp. Med. 1998 187:813 PubMed

Bottino C, Sivori S, Vitale M, Cantoni C, Falco M, Pende D, Morelli L, Augugliaro R, Semenzato G, Biassoni R, Moretta L and Moretta A. A novel surface molecule homologous to the p58/p50 family of receptors is selectively expressed on a subset of human natural killer cells and induces both triggering of cell functions and proliferation. Eur. J. Immunol. 1996 26:1816 PubMed

Braud VM, Allan DS, O'Callaghan CA, Soderstrom K, D'Andrea A, Ogg GS, Lazetic S, Young NT, Bell JI, Phillips JH, Lanier LL and McMichael AJ. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 1998 391:795 PubMed

Burshtyn DN, Scharenberg AM, Wagtmann N, Rajagopalan S, Berrada K, Yi T, Kinet JP and Long EO. Recruitment of tyrosine phosphatase HCP by the killer cell inhibitor receptor. Immunity 1996 4:77 PubMed

Burshtyn DN, Yang W, Yi T and Long EO. A novel phosphotyrosine motif with a critical amino acid at position -2 for the SH2 domain-mediated activation of the tyrosine phosphatase SHP-1. J. Biol. Chem. 1997 272:13066 PubMed

Cambiaggi A, Verthuy C, Naquet P, Romagne F, Ferrier P, Biassoni R, Moretta A, Moretta L, Vivier E. Natural killer cell acceptance of H-2 mismatch bone marrow grafts in transgenic mice expressing HLA-Cw3 specific killer cell inhibitory receptor. Proc. Natl. Acad. Sci. U.S.A. 1997 94:8088 PubMed**

Campbell KS, Dessing M, Lopez-Botet M, Cella M and Colonna M. Tyrosine phosphorylation of a human killer inhibitory receptor recruits protein tyrosine phosphatase 1C. J. Exp. Med. 1996 184:93 PubMed

Cantoni C, Verdiani S, Falco M, Pessino A, Cilli M, Conte R, Pende D, Ponte M, Mikaelsson MS, Moretta L, Biassoni R. p49, a putative HLA class I-specific inhibitory NK receptor belonging to the immunoglobulin superfamily. Eur. J. Immunol. 1998 28:1980 PubMed

Carretero et al. 1998. In: Leucocyte typing VI. Edited by Kishimoto et al. Garland Publishing Inc. New York & London. p. 294

Castells MC, Wu X, Arm JP, Austen KF and Katz HR. Cloning of the gp49B gene of the immunoglobulin superfamily and demonstration that one of its two products is an early-expressed mast cell surface protein originally described as gp49. J. Biol. Chem. 1994 269:8393 PubMed

Colonna M, Navarro F, Bellon T, Llano M, Garcia P, Samaridis J, Angman L, Cella M, Lopez-Botet M. A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J. Exp. Med. 1997 186:1809 PubMed**

Colonna M and Samaridis J. Cloning of immunoglobulin-superfamily members associated with HLA-C and HLA-B recognition by human natural killer cells. Science 1995 268:405 PubMed

Cosman D, Fanger N, Borges L, Kubin M, Chin W, Peterson L and Hsu ML. A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity 1997 7:273 PubMed

D'Andrea A, Chang C, Franz-Bacon K, McClanahan T, Phillips JH and Lanier LL. Molecular cloning of NKB1. A natural killer cell receptor for HLA-B allotypes. J. Immunol. 1995 155:2306 PubMed

D'Andrea A, Chang C, Phillips JH and Lanier LL. Regulation of T cell lymphokine production by killer cell inhibitory receptor recognition of self HLA class I alleles. J. Exp. Med. 1996 184:789 PubMed

Dohring C, Samaridis J and Colonna M. Alternatively spliced forms of human killer inhibitory receptors. Immunogenetics 1996a 44:227 PubMed

Dohring C, Scheidegger D, Samaridis J, Cella M and Colonna M. A human killer inhibitory receptor specific for HLA-A1,2. J. Immunol. 1996b 156:3098 PubMed

Fan QR, Mosyak L, Winter CC, Wagtmann N, Long EO and Wiley DC. Structure of the inhibitory receptor for human natural killer cells resembles haematopoietic receptors. Nature 1997 389:96 PubMed

Ferrini S, Cambiaggi A, Meazza R, Sforzini S, Marciano S, Mingari MC and Moretta L. T cell clones expressing the natural killer cell-related p58 receptor molecule display heterogeneity in phenotypic properties and p58 function. Eur. J. Immunol. 1994 24:2294 PubMed

Fry AM, Lanier LL and Weiss A. Phosphotyrosines in the killer cell inhibitory receptor motif of NKB1 are required for negative signaling and for association with protein tyrosine phosphatase 1C. J. Exp. Med. 1996 184:295 PubMed

George T, Yu YY, Liu J, Davenport C, Lemieux S, Stoneman E, Mathew PA, Kumar V and Bennett M. Allorecognition by murine natural killer cells: lysis of T-lymphoblasts and rejection of bone-marrow grafts. Immunol. Rev. 1997 155:29 PubMed

Gumperz JE, Valiante NM, Parham P, Lanier LL and Tyan D. Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I receptor among individuals of different human histocompatibility leukocyte antigens types appear genetically regulated, but not linked to major histocompatibililty complex haplotype. J. Exp. Med. 1996 183:1817 PubMed

Hayami K, Fukuta D, Nishikawa Y, Yamashita Y, Inui M, Ohyama Y, Hikida M, Ohmori H and Takai T. Molecular cloning of a novel murine cell-surface glycoprotein homologous to killer cell inhibitory receptors. J. Biol. Chem. 1997 272:7320 PubMed

Ikeda H, Lethe B, Lehmann F, van Baren N, Baurain JF, de Smet C, Chambost H, Vitale M, Moretta A, Boon T and Coulie PG. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity 1997 6:199 PubMed

Kim J, Chwae YJ, Kim MY, Choi IH, Park JH and Kim SJ. Molecular basis of HLA-C recognition by p58 natural killer cell inhibitory receptors. J. Immunol. 1997 159:3875 PubMed

Kubagawa H, Burrows PD and Cooper MD. A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells. Proc. Natl. Acad. Sci. U.S.A. 1997 94:5261 PubMed

Lanier LL, Corliss BC, Wu J, Leong C and Phillips JH. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 1998 391:703 PubMed

Lanier LL, Gumperz JE, Parham P, Melero I, Lopez-Botet M, Phillips JH. The NKB1 and HP-3E4 NK cells receptors are structurally distinct glycoproteins and independently recognize polymorphic HLA-B and HLA-C molecules. J. Immunol. 1995 154:3320 PubMed**

Lazetic S, Chang C, Houchins JP, Lanier LL and Phillips JH. Human natural killer cell receptors involved in MHC class I recognition are disulfide-linked heterodimers of CD94 and NKG2 subunits. J. Immunol. 1996 157:4741 PubMed

Lee N, Llano M, Carretero M, Ishitani A, Navarro F, Lopez-Botet M and Geraghty DE. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc. Natl. Acad. Sci. U.S.A. 1998 95:5199 PubMed

Litwin V, Gumperz J, Parham P, Phillips JH and Lanier LL. NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules. J. Exp. Med. 1994 180:537 PubMed

Maliszewski CR, March CJ, Schoenborn MA, Gimpel S and Shen L. Expression cloning of a human Fc receptor for IgA. J. Exp. Med. 1990 172:1665 PubMed

Mandelboim O, Davis DM, Reyburn HT, Vales-Gomez M, Sheu EG, Pazmany L and Strominger JL. Enhancement of class II-restricted T cell responses by costimulatory NK receptors for class I MHC proteins. Science 1996 274:2097 PubMed

Melero I, Salmeron A, Balboa MA, Aramburu J and Lopez-Botet M. Tyrosine kinase-dependent activation of human NK cell functions upon stimulation through a 58-kDa surface antigen selectively expressed on discrete subsets of NK cells and T lymphocytes. J Immunol 1994 152:1662 PubMed

Meyaard L, Adema GJ, Chang C, Woollatt E, Sutherland GR, Lanier LL and Phillips JH. LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes. Immunity 1997 7:283 PubMed

Mingari MC, Schiavetti F, Ponte M, Vitale C, Maggi E, Romagnani S, Demarest J, Pantaleo G, Fauci AS, Moretta L. Human CD8+ T lymphocyte subsets that express HLA class I-specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations. Proc. Natl. Acad. Sci. U. S. A. 1996 93:12433 PubMed**

Moretta A, Bottino C, Pende D, Tripodi G, Tambussi G, Viale O, Orengo A, Barbaresi M, Merli A, Ciccone E, et al. Identification of four subsets of human CD3-CD16+ natural killer (NK) cells by the expression of clonally distributed functional surface molecules: correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition. J. Exp. Med. 1990a 172:1589 PubMed**

Moretta A, Sivori S, Vitale M, Pende D, Morelli L, Augugliaro R, Bottino C and Moretta L. Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. J. Exp. Med. 1995 182:875 PubMed

Moretta A, Tambussi G, Bottino C, Tripodi G, Merli A, Ciccone E, Pantaleo G and Moretta L. A novel surface antigen expressed by a subset of human CD3- CD16+ natural killer cells. Role in cell activation and regulation of cytolytic function. J. Exp. Med. 1990b 171:695 PubMed

Moretta A, Vitale M, Bottino C, Orengo AM, Morelli L, Augugliaro R, Barbaresi M, Ciccone E and Moretta L. P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities. J. Exp. Med. 1993 178:597 PubMed

Olcese L, Cambiaggi A, Semenzato G, Bottino C, Moretta A and Vivier E. Human killer cell activatory receptors for MHC class I molecules are included in a multimeric complex expressed by natural killer cells. J. Immunol. 1997 158:5083 PubMed

Olcese L, Lang P, Vely F, Cambiaggi A, Marguet D, Blery M, Hippen KL, Biassoni R, Moretta A, Moretta L, Cambier JC and Vivier E. Human and mouse killer-cell inhibitory receptors recruit PTP1C and PTP1D protein tyrosine phosphatases. J. Immunol. 1996 156:4531 PubMed

Pende D, Biassoni R, Cantoni C, Verdiani S, Falco M, di Donato C, Accame L, Bottino C, Moretta A and Moretta L. The natural killer cell receptor specific for HLA-A allotypes: a novel member of the p58/p70 family of inhibitory receptors that is characterized by three immunoglobulin-like domains and is expressed as a 140-kD disulphide-linked dimer. J. Exp. Med. 1996 184:505 PubMed

Rajagopalan S, Winter CC, Wagtmann N and Long EO. The Ig-related killer cell inhibitory receptor binds zinc and requires zinc for recognition of HLA-C on target cells. J. Immunol. 1995 155:4143 PubMed

Samaridis J and Colonna M. Cloning of novel immunoglobulin superfamily receptors expressed on human myeloid and lymphoid cells: structural evidence for new stimulatory and inhibitory pathways. Eur. J. Immunol. 1997 27:660 PubMed

Selvakumar A, Steffens U and Dupont B. NK cell receptor gene of the KIR family with two IG domains but highest homology to KIR receptors with three IG domains. Tissue Antigens 1996 48:285 PubMed

Selvakumar A, Steffens U and Dupont B. Polymorphism and domain variability of human killer cell inhibitory receptors. Immunol. Rev. 1997a 155:183 PubMed

Selvakumar A, Steffens U, Palanisamy N, Chaganti RS and Dupont B. Genomic organization and allelic polymorphism of the human killer cell inhibitory receptor gene KIR103. Tissue Antigens 1997b 49:564 PubMed

Valiante NM, Uhrberg M, Shilling HG, Lienert-Weidenbach K, Arnett KL, D'Andrea A, Phillips JH, Lanier LL and Parham P. Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. Immunity 1997 7:739 PubMed

Vitale M, Sivori S, Pende D, Augugliaro R, Di Donato C, Amoroso A, Malnati M, Bottino C, Moretta L and Moretta A. Physical and functional independency of p70 and p58 natural killer (NK) cell receptors for HLA class I: their role in the definition of different groups of alloreactive NK cell clones. Proc. Natl. Acad. Sci. U.S.A. 1996 93:1453 PubMed

Wagtmann N, Biassoni R, Cantoni C, Verdiani S, Malnati MS, Vitale M, Bottino C, Moretta L, Moretta A and Long EO. Molecular clones of the p58 NK cell receptor reveal immunoglobulin-related molecules with diversity in both the extra- and intracellular domains. Immunity 1995a 2:439 PubMed

Wagtmann N, Rajagopalan S, Winter CC, Peruzzi M and Long EO. Killer cell inhibitory receptors specific for HLA-C and HLA-B identified by direct binding and by functional transfer. Immunity 1995b 3:801 PubMed

Wagtmann N, Rojo S, Eichler E, Mohrenweiser H and Long EO. A new human gene complex encoding the killer cell inhibitory receptors and related monocyte/macrophage receptors. Curr. Biol. 1997 7:615 PubMed

Wilson MJ, Torkar M and Trowsdale J. Genomic organization of a human killer cell inhibitory receptor gene. Tissue Antigens 1997 49:574 PubMed

WWW RESOURCES