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Gene Review

CXCR6  -  chemokine (C-X-C motif) receptor 6

Homo sapiens

Synonyms: BONZO, C-X-C chemokine receptor type 6, CD186, CDw186, CXC-R6, ...
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Disease relevance of CXCR6

  • HIV-2 isolates from aviremic individuals commonly use as coreceptors CCR5, GPR15, and CXCR6, as well as an unidentified receptor expressed by U87 cells [1].
  • CCR5, GPR15, and CXCR6 are major coreceptors of human immunodeficiency virus type 2 variants isolated from individuals with and without plasma viremia [1].
  • In 2 transmitting mothers from whom sequential HIV-1 isolates were available, viral coreceptor usage evolved from CCR5 monotropic to CCR5/Bonzo dual tropic during pregnancy, and in 1 case transmission of this virus could be documented [2].
  • Reports have implicated Bonzo/STRL33/TYMSTR to be an additional alternative coreceptor for HIV and especially SIV infection [3].
  • In addition to the chemokine, its receptor CXCR6 could be detected by quantitative RT-PCR in human glioma tissue, cultivated murine astrocytes and at a lower level in microglial cells [4].

High impact information on CXCR6

  • Other receptors with a more restricted cellular distribution, such as CCR2b, CCR3 and STRL33, can also function as co-receptors for selected viral isolates [5].
  • An update of the International Union of Pharmacology nomenclature for chemokines is outlined, defining one new receptor type, CXCR6, and disqualifying the putative receptor, CCR11 [6].
  • Of greatest interest, STRL33, in contrast with CXCR4 or CCR5, was able to function as a cofactor for fusion mediated by Envs from both T cell line-tropic and macrophage-tropic HIV-1 strains [7].
  • Despite the sequence similarities between STRL33 and chemokine receptors, STRL33-transfected cell lines did not respond to any in a panel of chemokines [7].
  • When transfected into nonhuman NIH 3T3 cells expressing human CD4, the STRL33 cDNA rendered these cells competent to fuse with cells expressing HIV-1 envelope glycoproteins (Envs) [7].

Biological context of CXCR6

  • The Th2-associated chemoattractant receptors CRTh2 and CCR3 were up-regulated with slower kinetics compared to the Th1-associated receptors CXCR3 and CXCR6, consistent with a different kinetics and efficiency of polarization [8].
  • Down-regulation of cell surface CXCR6 expression during T cell activation is predominantly mediated by calcineurin [9].
  • A recombinant version of CXCL16 fails to mediate chemotaxis to all known chemokine receptor transfectants tested but does mediate robust chemotaxis, high affinity binding, and calcium mobilization to Bonzo receptor transfectants, indicating that this is a unique receptor ligand interaction [10].
  • In several cases, a broad tropism was observed during the course of infection, with a frequent usage of BOB and Bonzo in addition to CCR5 [11].
  • However, in MBP-specific TCL, CXCR6 was found to be the best marker of conversion to the Tem phenotype [12].

Anatomical context of CXCR6

  • Moreover, CCR4 and CXCR6 were preferentially induced in T cells activated by mDC and pDC, respectively [8].
  • The immunodeficiency virus coreceptor, Bonzo/STRL33/TYMSTR, is expressed by macaque and human skin- and blood-derived dendritic cells [3].
  • Immobilized CXC chemokine ligand (CXCL)16, a novel transmembrane-type chemokine and CXCR6 ligand, also directly induced adhesion of plasma cells without requiring G(alpha i) signaling or divalent cations [13].
  • CCR9 and CXCR6 have not been described previously on primary NK cells [14].
  • These results suggest that the interaction between SR-PSOX/CXCL16 and CXCR6 plays an important role in enhancing T(CM) cell responses by mature DCs in lymphoid tissues and in augmenting T(EM) cell responses by macrophages in peripheral inflamed tissues [15].

Associations of CXCR6 with chemical compounds

  • FK506 also blocked the decrease of CXCR6 expression caused by ionomycin, whereas staurosporine or PP2 had no effect on this decrease [9].
  • Furthermore, the flavoprotein inhibitor diphenyleniodonium chloride significantly attenuated LPS-mediated AP-1-dependent CXCR6 expression, as did inhibition of NOX4 NADPH oxidase by siRNA [16].
  • While bacterial lipopolysaccharide (LPS) has been shown to stimulate CXCL16 expression in SMC, its effects on CXCR6 are not known [16].
  • These results show that a serine residue located just outside of the cellular membrane in the N terminus of STRL33 is critical for SIV coreceptor function [17].

Physical interactions of CXCR6


Regulatory relationships of CXCR6


Other interactions of CXCR6

  • In vitro polarized T cell subsets including Th1, Th2, and Tr1 cells express functional Bonzo, suggesting expression of this receptor in chronic inflammation, which we further verified by demonstration of CXCL16-mediated migration of tonsil-derived CD4(+) T lymphocytes [10].
  • Strains of HIV-2, which are closely related to the SIVs, also often utilise CXCR4, CCR5, BOB and/or Bonzo [19].
  • Moreover, CCR7, whose expression was low on CXCR6(+) T cells, was little affected by any of these modes of activation [9].
  • Altogether, these data indicate that CXCR6 expression is down-regulated, independent of CCR5 or CD69 expression and of cytokine induction, by T cell activation signals that involve predominantly the Ca(2+)-dependent calcineurin pathway [9].
  • STRL33, A novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and T cell line-tropic HIV-1 [7].

Analytical, diagnostic and therapeutic context of CXCR6


  1. CCR5, GPR15, and CXCR6 are major coreceptors of human immunodeficiency virus type 2 variants isolated from individuals with and without plasma viremia. Blaak, H., Boers, P.H., Gruters, R.A., Schuitemaker, H., van der Ende, M.E., Osterhaus, A.D. J. Virol. (2005) [Pubmed]
  2. Coreceptor usage of HIV-1 isolates representing different genetic subtypes obtained from pregnant Cameroonian women. European Network for In Utero Transmission of HIV-1. Tscherning-Casper, C., Vödrös, D., Menu, E., Aperia, K., Fredriksson, R., Dolcini, G., Chaouat, G., Barré-Sinoussi, F., Albert, J., Fenyö, E.M. J. Acquir. Immune Defic. Syndr. (2000) [Pubmed]
  3. The immunodeficiency virus coreceptor, Bonzo/STRL33/TYMSTR, is expressed by macaque and human skin- and blood-derived dendritic cells. Ignatius, R., Wei, Y., Beaulieu, S., Gettie, A., Steinman, R.M., Pope, M., Mojsov, S. AIDS Res. Hum. Retroviruses (2000) [Pubmed]
  4. Enhanced expression and shedding of the transmembrane chemokine CXCL16 by reactive astrocytes and glioma cells. Ludwig, A., Schulte, A., Schnack, C., Hundhausen, C., Reiss, K., Brodway, N., Held-Feindt, J., Mentlein, R. J. Neurochem. (2005) [Pubmed]
  5. In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. Scarlatti, G., Tresoldi, E., Björndal, A., Fredriksson, R., Colognesi, C., Deng, H.K., Malnati, M.S., Plebani, A., Siccardi, A.G., Littman, D.R., Fenyö, E.M., Lusso, P. Nat. Med. (1997) [Pubmed]
  6. International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature. Murphy, P.M. Pharmacol. Rev. (2002) [Pubmed]
  7. STRL33, A novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and T cell line-tropic HIV-1. Liao, F., Alkhatib, G., Peden, K.W., Sharma, G., Berger, E.A., Farber, J.M. J. Exp. Med. (1997) [Pubmed]
  8. Kinetics and expression patterns of chemokine receptors in human CD4+ T lymphocytes primed by myeloid or plasmacytoid dendritic cells. Langenkamp, A., Nagata, K., Murphy, K., Wu, L., Lanzavecchia, A., Sallusto, F. Eur. J. Immunol. (2003) [Pubmed]
  9. Down-regulation of cell surface CXCR6 expression during T cell activation is predominantly mediated by calcineurin. Koprak, S., Matheravidathu, S., Springer, M., Gould, S., Dumont, F.J. Cell. Immunol. (2003) [Pubmed]
  10. Expression cloning of the STRL33/BONZO/TYMSTRligand reveals elements of CC, CXC, and CX3C chemokines. Wilbanks, A., Zondlo, S.C., Murphy, K., Mak, S., Soler, D., Langdon, P., Andrew, D.P., Wu, L., Briskin, M. J. Immunol. (2001) [Pubmed]
  11. Broad spectrum of coreceptor usage and rapid disease progression in HIV-1-infected individuals from Central African Republic. Bégaud, E., Feindirongai, G., Versmisse, P., Ipero, J., Léal, J., Germani, Y., Morvan, J., Fleury, H., Müller-Trutwin, M., Barré-Sinoussi, F., Pancino, G. AIDS Res. Hum. Retroviruses (2003) [Pubmed]
  12. Chemokine receptor expression on MBP-reactive T cells: CXCR6 is a marker of IFNgamma-producing effector cells. Calabresi, P.A., Yun, S.H., Allie, R., Whartenby, K.A. J. Neuroimmunol. (2002) [Pubmed]
  13. Cutting edge: profile of chemokine receptor expression on human plasma cells accounts for their efficient recruitment to target tissues. Nakayama, T., Hieshima, K., Izawa, D., Tatsumi, Y., Kanamaru, A., Yoshie, O. J. Immunol. (2003) [Pubmed]
  14. Evidence for NK cell subsets based on chemokine receptor expression. Berahovich, R.D., Lai, N.L., Wei, Z., Lanier, L.L., Schall, T.J. J. Immunol. (2006) [Pubmed]
  15. Distribution and kinetics of SR-PSOX/CXCL16 and CXCR6 expression on human dendritic cell subsets and CD4+ T cells. Tabata, S., Kadowaki, N., Kitawaki, T., Shimaoka, T., Yonehara, S., Yoshie, O., Uchiyama, T. J. Leukoc. Biol. (2005) [Pubmed]
  16. TLR4-NOX4-AP-1 signaling mediates lipopolysaccharide-induced CXCR6 expression in human aortic smooth muscle cells. Patel, D.N., Bailey, S.R., Gresham, J.K., Schuchman, D.B., Shelhamer, J.H., Goldstein, B.J., Foxwell, B.M., Stemerman, M.B., Maranchie, J.K., Valente, A.J., Mummidi, S., Chandrasekar, B. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  17. Simian immunodeficiency virus utilizes human and sooty mangabey but not rhesus macaque STRL33 for efficient entry. Pöhlmann, S., Lee, B., Meister, S., Krumbiegel, M., Leslie, G., Doms, R.W., Kirchhoff, F. J. Virol. (2000) [Pubmed]
  18. CXCL16-mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway. Ruth, J.H., Haas, C.S., Park, C.C., Amin, M.A., Martinez, R.J., Haines, G.K., Shahrara, S., Campbell, P.L., Koch, A.E. Arthritis Rheum. (2006) [Pubmed]
  19. G protein-coupled receptors in HIV and SIV entry: new perspectives on lentivirus-host interactions and on the utility of animal models. Unutmaz, D., KewalRamani, V.N., Littman, D.R. Semin. Immunol. (1998) [Pubmed]
  20. HIV type 1 molecular clones able to use the Bonzo/STRL-33 coreceptor for virus entry. Zhang, Y.J., Zhang, L., Ketas, T., Korber, B.T., Moore, J.P. AIDS Res. Hum. Retroviruses (2001) [Pubmed]
  21. Pathogenic role of the CXCL16-CXCR6 pathway in rheumatoid arthritis. Nanki, T., Shimaoka, T., Hayashida, K., Taniguchi, K., Yonehara, S., Miyasaka, N. Arthritis Rheum. (2005) [Pubmed]
  22. Expression of CXCR6 and its ligand CXCL16 in the lung in health and disease. Morgan, A.J., Guillen, C., Symon, F.A., Huynh, T.T., Berry, M.A., Entwisle, J.J., Briskin, M., Pavord, I.D., Wardlaw, A.J. Clin. Exp. Allergy (2005) [Pubmed]
  23. CXCR6 within T-helper (Th) and T-cytotoxic (Tc) type 1 lymphocytes in Graves' disease (GD). Aust, G., Kamprad, M., Lamesch, P., Schmücking, E. Eur. J. Endocrinol. (2005) [Pubmed]
  24. Cloning and sequencing of cynomolgus macaque CCR3, GPR15, and STRL33: potential coreceptors for HIV type 1, HIV type 2, and SIV. Wade-Evans, A.M., Russell, J., Jenkins, A., Javan, C. AIDS Res. Hum. Retroviruses (2001) [Pubmed]
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