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Gene Review

Klra3  -  killer cell lectin-like receptor,...

Mus musculus

Synonyms: 5E6, Killer cell lectin-like receptor 3, Ly-49c, Ly49C, Ly49c, ...
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Disease relevance of Klra3

  • Since NK-1.1 and NK-2.1 are also expressed on 2-3% of spleen cells of positive strains we suggest that all three alloantigens identify the NK cells in normal mouse spleen which lyse the lymphoma target cell line YAC [1].

High impact information on Klra3

  • We show here that the Ly49A and Ly49C NK-cell receptors are each subject to allelic exclusion [2].
  • Expression of Ly49A and Ly49C, another member of the Ly49 family with distinct MHC specificity, define subpopulations of NK cells that are only partly overlapping [2].
  • During the first days after birth, few or no splenic NK cells express Ly49A, Ly49C, Ly49G2, or Ly49I receptors [3].
  • Flow cytometric analyses of COS cells transfected with the two cDNAs showed that the 5E6 antibody binds to both Ly-49 molecules, while another anti-Ly-49C antibody, 4LO3311, binds to the newly described Ly-49C but not the previously reported Ly-49CB6 [4].
  • Thus, there appears to be allelic exclusion of 5E6 expression that may be related to the ability of F1 hybrid mice to reject parental H-2d bone marrow cell grafts [5].

Biological context of Klra3

  • Gene order and intergene distances (in cM) were: centromere-Cd94/Nkg2d-(0.05)-Ly49a/Ly49c/Ly49 g/Cmv1-(0. 3)-Prp/Kap/D6Mit13/111/219 [6].
  • 5E6 is nearly identical to Ly-49C; the deduced amino acid sequence reveals a polypeptide of 266 amino acids with a molecular weight of 31,284 that contains multiple cysteine residues to explain its disulfide-linked homodimer structure and five potential N-linked glycosylation sites [5].
  • Here, we isolated and cloned the gene encoding 5E6 and determined the nucleotide sequence of the cDNA [5].
  • Chromosomal mapping indicates that 5E6 is located within the NK gene complex on chromosome 6 [5].
  • Blockade of Ly49C and I inhibitory receptors using F(ab')(2) fragments of the 5E6 monoclonal antibody (mAb) resulted in increased cytotoxicity against syngeneic tumors and decreased tumor cell growth in vitro [7].

Anatomical context of Klra3

  • These results suggest that reduction of Ly49C/I+ NK1.1+gamma/delta T cells in beta2m+/+ mice is at least partly due to the down-modulation by MHC class I molecules on BM-derived haematopoietic cells or radioresistant cells in the thymus [8].
  • The antibodies 5E6 and 34-1-2S (anti-class I MHC) inhibited the binding of Ly-49C to an H-2s cell line [9].
  • In addition, we find a several-fold increase in Ly49C/I-expressing NKT cells in adult thymus, apparently independent of MHC class I molecules [10].
  • This NK-1.1- CD3- LFA-3+ B220+ population, when stimulated with IL-2 and co-cultured with supportive syngeneic stromal cells, generated populations of NK-1.1+ Ly49A+ Ly49C/I+ CD3- mature natural killer cells [11].

Associations of Klra3 with chemical compounds

  • With two other targets, E male G2 and RBL-5, neither serum produced significant depletion of activity, Analysis of SC indirectly labeled with either NK-1.1 or NK-2.1 antiserum and fluorescein-labeled goat anti-mouse Ig, however, did not detect significant differences between NK-1+ and NK-2+ cell populations [12].
  • 2) The NK(YAC-1) precursors lack the surface antigens (NK-2.1, asialo GM1, Qa-5, Thy-1) that are characteristically seen on mature NK cells [13].
  • Unlike NK cells, the cells capable of lysing FLD-3 cells in vitro were insensitive to antibodies directed against NK-2.1 or Thy-1.2 antigens (plus complement) and to pretreatment of mice in vivo with silica particles, 89Sr or estradiol [14].
  • The former mAbs recognized epitopes present on CaE major allergen and also shared by other components. mAb 5E6 showed a spread reactivity on CaE, with exclusion of the major allergen [15].

Other interactions of Klra3

  • Using a site-directed mutagenesis approach, we have targeted residues conserved in receptors binding to m157 (Ly49H and Ly49I(129)) but different from receptors lacking m157 recognition (Ly49C, Ly49I(B6), and Ly49U) [16].
  • In this manner, we identified five new potential Ly49 genes which have been tentatively termed Ly49j-n. Ly49j, k, and n belong to the Ly49c-related subfamily, whereas Ly49l and Ly49m are most similar to Ly49d and g, respectively [17].
  • 5E6 is a cell surface molecule expressed on a subpopulation of murine natural killer (NK) cells that are involved in the specific rejection of H-2d or H-2f (hemopoietic histocompatibility determinant 2) bone marrow cell grafts [5].
  • The expression levels of H60 on the target cells determined the extent to which the inhibition by Ly49C/I receptors can be overridden [18].
  • Over 75% of them expressed Ly49C, I, or NKG2A, which are thought to recognize self-class I MHC (H-2b) [19].

Analytical, diagnostic and therapeutic context of Klra3

  • Here we show by Southern blotting that at least two additional new sequences exist in C57BL/6 mice that are also closely related to Ly49c in the carbohydrate recognition domain [17].
  • Treatment of leukemia-bearing mice with 5E6 F(ab')(2) fragments or adoptive transfer of NK cells treated ex vivo with the F(ab')(2) resulted in significant increases in survival [7].
  • Therefore, down-regulation of developing Ly49A+ and Ly49C/I+ chimeric NK cell frequencies by cognate ligands within 7-8 wk after BM transplantation may be important for successful engraftment [20].
  • Cross-reactivity was evaluated by ELISA inhibition and immunoblotting. mAbs 2D5 and 4A6 recognized periodate-resistant epitopes, whereas the mAb 5E6 reacted with a periodate-sensitive determinant [15].
  • We show that treatment of interleukin 2-activated C57BL/6 (B6, H2b) SCID-mouse NK cells with 5E6 F(ab')2 fragments during 48-hour coculture resulted in autoreactivity against syngeneic BMCs as demonstrated by suppression of myeloid reconstitution on day 14 post-BMT [21].


  1. Studies on natural killer (NK) cells IV NK-3.1: a new NK cell specific alloantigen. Burton, R.C., Smart, Y.C., Thorn, R., Winn, H.J. Immunol. Cell Biol. (1989) [Pubmed]
  2. Allelic exclusion of Ly49-family genes encoding class I MHC-specific receptors on NK cells. Held, W., Roland, J., Raulet, D.H. Nature (1995) [Pubmed]
  3. Acquisition of Ly49 receptor expression by developing natural killer cells. Dorfman, J.R., Raulet, D.H. J. Exp. Med. (1998) [Pubmed]
  4. Heterogeneity among Ly-49C natural killer (NK) cells: characterization of highly related receptors with differing functions and expression patterns. Brennan, J., Lemieux, S., Freeman, J.D., Mager, D.L., Takei, F. J. Exp. Med. (1996) [Pubmed]
  5. Cloning and characterization of 5E6(Ly-49C), a receptor molecule expressed on a subset of murine natural killer cells. Stoneman, E.R., Bennett, M., An, J., Chesnut, K.A., Wakeland, E.K., Scheerer, J.B., Siciliano, M.J., Kumar, V., Mathew, P.A. J. Exp. Med. (1995) [Pubmed]
  6. Assessment of Cmv1 candidates by genetic mapping and in vivo antibody depletion of NK cell subsets. Depatie, C., Chalifour, A., Paré, C., Lee, S.H., Vidal, S.M., Lemieux, S. Int. Immunol. (1999) [Pubmed]
  7. Augmentation of antitumor effects by NK cell inhibitory receptor blockade in vitro and in vivo. Koh, C.Y., Blazar, B.R., George, T., Welniak, L.A., Capitini, C.M., Raziuddin, A., Murphy, W.J., Bennett, M. Blood (2001) [Pubmed]
  8. Thymus-dependent modulation of Ly49 inhibitory receptor expression on NK1.1+gamma/delta T cells. Hara, T., Nishimura, H., Hasegawa, Y., Yoshikai, Y. Immunology (2001) [Pubmed]
  9. Expression of different members of the Ly-49 gene family defines distinct natural killer cell subsets and cell adhesion properties. Brennan, J., Mager, D., Jefferies, W., Takei, F. J. Exp. Med. (1994) [Pubmed]
  10. MHC-dependent and -independent modulation of endogenous Ly49 receptors on NK1.1+ T lymphocytes directed by T-cell receptor type. Sköld, M., Stenström, M., Sidobre, S., Höglund, P., Kronenberg, M., Cardell, S. Immunology (2003) [Pubmed]
  11. IL-2-driven natural killer cell generation: role of anti-H-2b monoclonal antibodies and stromal cells in controlling quantitative and repertoire changes. Agostini, M., Di Marco, B., Spinicelli, S., Bruscoli, S., Delfino, D.V. Journal of chemotherapy (Florence, Italy) (2001) [Pubmed]
  12. Murine NK cell heterogeneity: subpopulations of C57BL/6 splenic NK cells detected by NK-1.1 and NK-2.1 antisera. Emmons, S.L., Pollack, S.B. Nat. Immun. Cell Growth Regul. (1985) [Pubmed]
  13. Origin and differentiation of natural killer cells. I. Characteristics of a transplantable NK cell precursor. Hackett, J., Bennett, M., Kumar, V. J. Immunol. (1985) [Pubmed]
  14. Lysis of FLD-3 Friend erythroleukemia cells in vitro and in vivo: effect of 89Sr treatment and Friend virus infection. Lust, J.A., Bennett, M., Kumar, V. Int. J. Cancer (1984) [Pubmed]
  15. Arizona cypress (Cupressus arizonica) pollen allergens. Identification of cross-reactive periodate-resistant and -sensitive epitopes with monoclonal antibodies. Barletta, B., Tinghino, R., Corinti, S., Afferni, C., Iacovacci, P., Mari, A., Pini, C., Di Felice, G. Allergy (1998) [Pubmed]
  16. Critical Residues at the Ly49 Natural Killer Receptor's Homodimer Interface Determine Functional Recognition of m157, a Mouse Cytomegalovirus MHC Class I-Like Protein. Kielczewska, A., Kim, H.S., Lanier, L.L., Dimasi, N., Vidal, S.M. J. Immunol. (2007) [Pubmed]
  17. Localization of five new Ly49 genes, including three closely related to Ly49c. McQueen, K.L., Freeman, J.D., Takei, F., Mager, D.L. Immunogenetics (1998) [Pubmed]
  18. NKG2D receptor-mediated NK cell function is regulated by inhibitory Ly49 receptors. Regunathan, J., Chen, Y., Wang, D., Malarkannan, S. Blood (2005) [Pubmed]
  19. Diversity of NK cell receptor repertoire in adult and neonatal mice. Kubota, A., Kubota, S., Lohwasser, S., Mager, D.L., Takei, F. J. Immunol. (1999) [Pubmed]
  20. Altered donor and recipient Ly49+ NK cell subsets in allogeneic H-2d --> H-2b and H-2b --> H-2d bone marrow chimeras. Korten, S., Wilk, E., Gessner, J.E., Meyer, D., Schmidt, R.E. J. Immunol. (1999) [Pubmed]
  21. NK inhibitory-receptor blockade for purging of leukemia: effects on hematopoietic reconstitution. Koh, C.Y., Raziuddin, A., Welniak, L.A., Blazar, B.R., Bennett, M., Murphy, W.J. Biol. Blood Marrow Transplant. (2002) [Pubmed]
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