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Gene Review

CD244  -  CD244 molecule, natural killer cell...

Homo sapiens

Synonyms: 2B4, NAIL, NK cell activation-inducing ligand, NK cell type I receptor protein 2B4, NKR2B4, ...
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Disease relevance of CD244


Psychiatry related information on CD244

  • For the 14 subjects who completed the study, clomipramine hydrochloride (mean +/- SD dose, 120 +/- 48 mg/d) was superior to desipramine hydrochloride (mean +/- SD dose, 135 +/- 53 mg/d) in decreasing nail biting as measured by a repeated-measures analysis of variance on the Nail Biting Severity, Nailbiting Impairment, and Clinical Progress scales [7].

High impact information on CD244

  • Engagement of receptor 2B4 by CD48 on insect cells induced weak polarization and no degranulation [8].
  • However, coengagement of 2B4 and CD16 by their respective ligands resulted in granule polarization and cytotoxicity in the absence of leukocyte functional antigen-1-mediated adhesion to target cells [8].
  • Two papers describing mice deficient in signaling lymphocyte activation molecule and 2B4 represent the first accounts of immune phenotypes in animals lacking members of the SLAM family of receptors [9].
  • Binding of activation receptor 2B4 to its ligand CD48 was not sufficient for Vav1 phosphorylation [10].

Chemical compound and disease context of CD244


Biological context of CD244

  • CD244-3BP2 interaction was direct and regulated by phosphorylation, as shown by a three-hybrid analysis in yeast and NK cells [15].
  • It binds a protein termed Src homology 2 domain-containing protein (SH2D1A) or signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which in turn has been proposed to function as a regulator of the 2B4-associated signal transduction pathway [4].
  • Human 2B4 was cloned based on sequence homology with mouse 2B4 [16].
  • Our results show that NK-resistant CC were sensitive to lysis by unstimulated peripheral blood lymphocytes in the presence of phytohemagglutin (PHA), to antibody-dependent cell cytotoxicity in presence of anti-Tja antibodies, and to monoclonal antibody redirected killing using anti-TR antibodies anti-CD16 and anti-CD244/2B4 [17].
  • However, when we introduced a three-base substitution mutation to disrupt the activator protein-1 binding site at (-106 to -100) in the 2B4 promoter, we found complete loss of transcriptional activity, including the two-fold increase due to PMA induction of PKC [18].

Anatomical context of CD244


Associations of CD244 with chemical compounds


Physical interactions of CD244


Enzymatic interactions of CD244

  • In this report, we show that NK cells from individuals with XLP but not healthy individuals fail to phosphorylate and thereby inactivate glycogen synthase kinase-3 (GSK-3) following 2B4 stimulation [27].
  • Human 2B4 became tyrosine phosphorylated following pervanadate-treatment of transfected cells and recruited SHP-2 [28].

Regulatory relationships of CD244

  • Instead, 2B4 is activated by binding to CD48, a GPI-anchored surface molecule that is widely expressed in the hemopoietic system [29].
  • 2B4-expressing target cells can efficiently stimulate NK cell cytotoxicity and IFN-gamma production [29].
  • In IL-2-activated NK cells with high SAP expression the triggering of 2B4 alone is sufficient to induce NK cell cytotoxicity, demonstrating a correlation between the regulated SAP expression and the function of 2B4 [30].
  • The data are consistent with a model in which the mechanism of signal transduction by CD244 is to regulate FYN kinase recruitment and/or activity and the outcome of CD48/CD244 interactions is determined by which other receptors are engaged [31].

Other interactions of CD244

  • We have recently identified CD48 as the high affinity counterreceptor for 2B4 in both mice and humans [1].
  • Thus, the positive signals attributed to the B cell activation of CD244 on murine NK cells appears to be more similar to the activity of CD244 on human cells [22].
  • 2B4 (CD244), a member of the CD2 subset of the Ig superfamily receptors, is expressed on all human NK cells, a subpopulation of T cells, basophils and monocytes [32].
  • Expression and regulation of the SLAM-family receptors SLAM, CD84, and 2B4, as well as the lytic effectors perforin and granzyme-B are normal in SAP-deficient CTLs [33].
  • Thus, cross-linking of 2B4 resulted in inhibition of both cytolytic activity and interferon-gamma (IFN-gamma) production [34].

Analytical, diagnostic and therapeutic context of CD244

  • This enhancement was concomitant with an increase in cytotoxicity due to CD244 ligation [15].
  • In this study, we report the molecular cloning and characterization of the human 2B4 (h2B4) promoter [1].
  • We isolated h2B4 genomic clones and PCR amplified the 5' untranslated region containing the promoter elements [1].
  • Two NK-related receptors showed significantly different levels of expression in heart transplant recipients: the cytotoxic effector, CD244, which was in a significantly increased proportion on T and NKT-like cells; and the activating receptor, CD161, which was expressed significantly less on NK and NKT-like cells, but more on T cells [35].
  • Molecular dissection of 2B4 signaling: implications for signal transduction by SLAM-related receptors [36].



  1. A prominent role for activator protein-1 in the transcription of the human 2B4 (CD244) gene in NK cells. Chuang, S.S., Pham, H.T., Kumaresan, P.R., Mathew, P.A. J. Immunol. (2001) [Pubmed]
  2. NK-associated receptors on CD8 T cells from treatment-naive HIV-infected individuals: defective expression of CD56. Tarazona, R., DelaRosa, O., Casado, J.G., Torre-Cisneros, J., Villanueva, J.L., Galiani, M.D., Peña, J., Solana, R. AIDS (2002) [Pubmed]
  3. Analysis of immune activation and clinical events in acute infectious mononucleosis. Williams, H., Macsween, K., McAulay, K., Higgins, C., Harrison, N., Swerdlow, A., Britton, K., Crawford, D. J. Infect. Dis. (2004) [Pubmed]
  4. X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells. Parolini, S., Bottino, C., Falco, M., Augugliaro, R., Giliani, S., Franceschini, R., Ochs, H.D., Wolf, H., Bonnefoy, J.Y., Biassoni, R., Moretta, L., Notarangelo, L.D., Moretta, A. J. Exp. Med. (2000) [Pubmed]
  5. The activatory receptor 2B4 is expressed in vivo by human CD8+ effector alpha beta T cells. Speiser, D.E., Colonna, M., Ayyoub, M., Cella, M., Pittet, M.J., Batard, P., Valmori, D., Guillaume, P., Liénard, D., Cerottini, J.C., Romero, P. J. Immunol. (2001) [Pubmed]
  6. 2B4(+) CD8(+) T cells play an inhibitory role against constrained HIV epitopes. Aldy, K.N., Horton, N.C., Mathew, P.A., Mathew, S.O. Biochem. Biophys. Res. Commun. (2011) [Pubmed]
  7. A double-blind comparison of clomipramine and desipramine treatment of severe onychophagia (nail biting). Leonard, H.L., Lenane, M.C., Swedo, S.E., Rettew, D.C., Rapoport, J.L. Arch. Gen. Psychiatry (1991) [Pubmed]
  8. Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells. Bryceson, Y.T., March, M.E., Barber, D.F., Ljunggren, H.G., Long, E.O. J. Exp. Med. (2005) [Pubmed]
  9. SLAM Family Receptors Regulate Immunity with and without SAP-related Adaptors. Veillette, A. J. Exp. Med. (2004) [Pubmed]
  10. Vav1 phosphorylation is induced by beta2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. Riteau, B., Barber, D.F., Long, E.O. J. Exp. Med. (2003) [Pubmed]
  11. Human prostate cancer expresses the low affinity insulin-like growth factor binding protein IGFBP-rP1. Degeorges, A., Wang, F., Frierson, H.F., Seth, A., Chung, L.W., Sikes, R.A. Cancer Res. (1999) [Pubmed]
  12. Dermatophyte test medium culture for evaluating toenail infections in patients with diabetes. Rich, P., Harkless, L.B., Atillasoy, E.S. Diabetes Care (2003) [Pubmed]
  13. Determination of the human liver UDP-glucuronosyltransferase 2B4 domains involved in the binding of UDP-glucuronic acid using photoaffinity labeling of fusion proteins. Pillot, T., Ouzzine, M., Fournel-Gigleux, S., Lafaurie, C., Tebbi, D., Treat, S., Radominska, A., Lester, R., Siest, G., Magdalou, J. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  14. Early experience with titanium elastic nails in a trauma unit. Shah, M.H., Heffernan, G., McGuinness, A.J. Irish medical journal. (2003) [Pubmed]
  15. The adaptor protein 3BP2 binds human CD244 and links this receptor to Vav signaling, ERK activation, and NK cell killing. Saborit-Villarroya, I., Del Valle, J.M., Romero, X., Esplugues, E., Lauzurica, P., Engel, P., Martín, M. J. Immunol. (2005) [Pubmed]
  16. Of mice and men: different functions of the murine and human 2B4 (CD244) receptor on NK cells. Vaidya, S.V., Mathew, P.A. Immunol. Lett. (2006) [Pubmed]
  17. Human choriocarcinoma cell resistance to natural killer lysis due to defective triggering of natural killer cells. Avril, T., Iochmann, S., Brand, D., Bardos, P., Watier, H., Thibault, G. Biol. Reprod. (2003) [Pubmed]
  18. Protein kinase C is involved in 2B4 (CD244)-mediated cytotoxicity and AP-1 activation in natural killer cells. Chuang, S.S., Lee, J.K., Mathew, P.A. Immunology (2003) [Pubmed]
  19. Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244). Eissmann, P., Beauchamp, L., Wooters, J., Tilton, J.C., Long, E.O., Watzl, C. Blood (2005) [Pubmed]
  20. Crystal Structure and Binding Properties of the CD2 and CD244 (2B4)-binding Protein, CD48. Evans, E.J., Castro, M.A., O'brien, R., Kearney, A., Walsh, H., Sparks, L.M., Tucknott, M.G., Davies, E.A., Carmo, A.M., van der Merwe, P.A., Stuart, D.I., Jones, E.Y., Ladbury, J.E., Ikemizu, S., Davis, S.J. J. Biol. Chem. (2006) [Pubmed]
  21. 2B4 (CD244) is expressed and functional on human eosinophils. Munitz, A., Bachelet, I., Fraenkel, S., Katz, G., Mandelboim, O., Simon, H.U., Moretta, L., Colonna, M., Levi-Schaffer, F. J. Immunol. (2005) [Pubmed]
  22. B cell induction of IL-13 expression in NK cells: role of CD244 and SLAM-associated protein. Gao, N., Schwartzberg, P., Wilder, J.A., Blazar, B.R., Yuan, D. J. Immunol. (2006) [Pubmed]
  23. Mutational analysis of the human 2B4 (CD244)/CD48 interaction: Lys68 and Glu70 in the V domain of 2B4 are critical for CD48 binding and functional activation of NK cells. Mathew, S.O., Kumaresan, P.R., Lee, J.K., Huynh, V.T., Mathew, P.A. J. Immunol. (2005) [Pubmed]
  24. NK cell inhibitory receptors prevent tyrosine phosphorylation of the activation receptor 2B4 (CD244). Watzl, C., Stebbins, C.C., Long, E.O. J. Immunol. (2000) [Pubmed]
  25. Association of the X-linked lymphoproliferative disease gene product SAP/SH2D1A with 2B4, a natural killer cell-activating molecule, is dependent on phosphoinositide 3-kinase. Aoukaty, A., Tan, R. J. Biol. Chem. (2002) [Pubmed]
  26. 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48. Brown, M.H., Boles, K., van der Merwe, P.A., Kumar, V., Mathew, P.A., Barclay, A.N. J. Exp. Med. (1998) [Pubmed]
  27. Role for glycogen synthase kinase-3 in NK cell cytotoxicity and X-linked lymphoproliferative disease. Aoukaty, A., Tan, R. J. Immunol. (2005) [Pubmed]
  28. Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP. Tangye, S.G., Lazetic, S., Woollatt, E., Sutherland, G.R., Lanier, L.L., Phillips, J.H. J. Immunol. (1999) [Pubmed]
  29. CD48 stimulation by 2B4 (CD244)-expressing targets activates human NK cells. Messmer, B., Eissmann, P., Stark, S., Watzl, C. J. Immunol. (2006) [Pubmed]
  30. Modulation of 2B4 (CD244) activity and regulated SAP expression in human NK cells. Endt, J., Eissmann, P., Hoffmann, S.C., Meinke, S., Giese, T., Watzl, C. Eur. J. Immunol. (2007) [Pubmed]
  31. Direct and indirect interactions of the cytoplasmic region of CD244 (2B4) in mice and humans with FYN kinase. Clarkson, N.G., Simmonds, S.J., Puklavec, M.J., Brown, M.H. J. Biol. Chem. (2007) [Pubmed]
  32. 2B4 (CD244)-mediated activation of cytotoxicity and IFN-gamma release in human NK cells involves distinct pathways. Chuang, S.S., Kumaresan, P.R., Mathew, P.A. J. Immunol. (2001) [Pubmed]
  33. SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. Dupré, L., Andolfi, G., Tangye, S.G., Clementi, R., Locatelli, F., Aricò, M., Aiuti, A., Roncarolo, M.G. Blood (2005) [Pubmed]
  34. Analysis of natural killer cells isolated from human decidua: evidence that 2B4 (CD244) functions as an inhibitory receptor and blocks NK-cell function. Vacca, P., Pietra, G., Falco, M., Romeo, E., Bottino, C., Bellora, F., Prefumo, F., Fulcheri, E., Venturini, P.L., Costa, M., Moretta, A., Moretta, L., Mingari, M.C. Blood (2006) [Pubmed]
  35. Modulation of natural killer (NK) receptors on NK (CD3-/CD56+), T (CD3+/CD56-) and NKT-like (CD3+/CD56+) cells after heart transplantation. Aguilar, P., Mathieu, C.P., Clerc, G., Ethevenot, G., Fajraoui, M., Mattei, S., Faure, G.C., Bene, M.C. J. Heart Lung Transplant. (2006) [Pubmed]
  36. Molecular dissection of 2B4 signaling: implications for signal transduction by SLAM-related receptors. Chen, R., Relouzat, F., Roncagalli, R., Aoukaty, A., Tan, R., Latour, S., Veillette, A. Mol. Cell. Biol. (2004) [Pubmed]
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