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Gene Review

GNG8  -  guanine nucleotide binding protein (G...

Homo sapiens

Synonyms: GNG9, GNGT9, Gamma-9, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8
 
 
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Disease relevance of GNG8

  • Recognition by human V gamma 9/V delta 2 T cells of a GroEL homolog on Daudi Burkitt's lymphoma cells [1].
  • Some of the V gamma 9/V delta 2 mycobacteria-specific clones are also stimulated by APC pulsed with different bacteria, such as Listeria monocytogenes and Escherichia coli, indicating that the population includes several different patterns of reactivity [2].
  • In CD3- T-ALL derived from immature T cells, V gamma genes more proximal to J gamma were frequently rearranged; V gamma 8, V gamma 9, V gamma 10, and V gamma 11 were used in 19 of 24 rearrangements [3].
  • Predominant activation and expansion of V gamma 9-bearing gamma delta T cells in vivo as well as in vitro in Salmonella infection [4].
  • Two leukemias that expressed the gamma protein rearranged V gamma 8 and V gamma 9 [5].
 

High impact information on GNG8

  • Stimulation of human V gamma 9/V delta 2 T cells is not restricted by human leukocyte antigens (HLA), including nonpolymorphic beta 2-microglobulin (beta 2M)-associated class Ib molecules [1].
  • However, in contrast to the clonal specificity of altered peptides antagonizing alpha beta T cells, all the tested V gamma 9/V delta 2 polyclonal cell lines and clones become unresponsive, a fact that may be relevant for the regulation of their response in vivo [6].
  • Stimulation with DPG results in partial early protein tyrosine phosphorylation and a prolonged, but reversible, state of unresponsiveness to agonist ligands in V gamma 9/V delta 2, but not in other T cells [6].
  • The larger set, representing 40-80% of all blood gamma/delta cells, is comprised of cells bearing the V gamma 9/C gamma 1 chain [2].
  • This heterodimer is very rare in the postnatal thymus, where a different and less restricted pairing of V gamma 9 and V delta 2 chains is found [7].
 

Biological context of GNG8

  • All human gamma delta T cells coexpressing the products of the variable (V) region T cell receptor (TCR) gene segments V gamma 9 and V delta 2 recognize antigens from mycobacterial extracts and Daudi cells [1].
  • As shown by DNA sequence analysis, V gamma 11 shares a 60% homology with V gamma 10 (third subgroup) and a 50% homology with V gamma 9 (second subgroup) but no appreciable homology with the V gamma segments from the first family [8].
  • Southern blot analysis of total PBL gamma cell lines and clones indicated that this major circulating subset of TCR gamma cells retained a TCR beta gene in germline configuration and preferentially expressed a single V gamma gene, V gamma 5 for patient 1 and V gamma 9 for patient 2 [9].
  • The TcR gamma/delta+ clones derived from one of these donors were all of the Ti gamma A+, delta-TCS1-, BB3+ phenotype indicating the exclusive use of the V gamma 9 and V delta 3 gene segments [10].
  • However, only half of RA patients showed elevated levels of the V gamma 9 gene expression in their PBMC [11].
 

Anatomical context of GNG8

  • When peripheral blood lymphocytes from normal individuals were cultured with live salmonella, gamma delta T cells were preferentially activated and expanded and most of them expressed V gamma 9 [4].
  • The transfectant T cells each expressing different gamma delta receptors all produced IL-2 after stimulation with plastic bound anti-CD3 Ab, but only those expressing V gamma 9 responded to stimulation with SEA in the presence of an autologous lymphoblastoid B cell line [12].
  • Together with the observation that V gamma 9/V delta 2+ cells represented the majority of T cells present in the fetal liver between 7 and 11 wk of development, our findings demonstrate that this subset of gamma delta T cells is a major, and presumably important, component of the human fetal immune system [13].
  • V gamma 9/V delta 2 T cells do not proliferate to other cell lines such as K562 or Molt4 that are sensitive to MHC-unrestricted cytolysis by NK cells and by most IL-2-activated gamma/delta T cell clones [14].
  • We suggest that measurement of V gamma 9 cell expansion within M. tb.-stimulated peripheral blood mononuclear cells provides a sensitive assay for the functional capacity of antigen (M. tb.)-specific CD4 Th1 cells in HIV-infected individuals [15].
 

Associations of GNG8 with chemical compounds

  • We report that one of these ligands, 2,3-diphosphoglyceric acid (DPG), which induces expansion of V gamma 9/V delta T cells ex vivo, antagonizes the same cell population after repetitive activation [6].
  • We suggested earlier that compounds synthesized by the 2-C:-methyl-D-erythritol 4-phosphate (MEP) pathway of isopentenyl pyrophosphate synthesis are responsible for the V gamma 9/V delta 2 T cell reactivity of many pathogens [16].
 

Regulatory relationships of GNG8

  • Upon SIV infection of the monkeys, we observed a transient increase of the percentage of total gamma delta T cell and the V gamma 9 subset. gamma delta T cells from infected animals also express more activation markers such as CD69, CD44 and the memory marker CD45RO [17].
  • Furthermore, IL-10 strongly inhibited the activation of V gamma 9 T cells among unfractionated PBMC responder cells [18].
  • Expression of V gamma 9 is not sufficient for the recognition of Daudi cells because most gamma/delta T cells expressing V delta 1 paired with V gamma 9 or other V gamma genes neither kill Daudi cells nor proliferate to Daudi [14].
 

Other interactions of GNG8

  • Patterns of chemokine receptor expression on peripheral blood gamma delta T lymphocytes: strong expression of CCR5 is a selective feature of V delta 2/V gamma 9 gamma delta T cells [19].
  • Panels of clones expressing V gamma 9 and V delta 2J1 produced significantly higher levels of TNF-alpha than clones not expressing V delta 2J1 and those expressing V delta 1J1 [20].
  • We have analyzed the respective roles of IL-10 and IL-12 in gamma delta T cell activation, using the selective expansion of V gamma 9 cells in Mtb- or Daudi-stimulated PBMC as a readout [21].
  • Finally, neutralization of endogenous IFN-gamma by Ab abrogated V gamma 9 cell responsiveness to Mtb but exerted only a minor inhibition of the reactivity toward Daudi cells [21].
  • We have investigated the dynamics in vitro of expansion of CD4 T cells and V gamma 9 cells in cultures of peripheral blood mononuclear cells stimulated with synthetic isopentenyl pyrophosphate (IPP) in the absence or presence of additional stimuli [22].
 

Analytical, diagnostic and therapeutic context of GNG8

References

  1. Recognition by human V gamma 9/V delta 2 T cells of a GroEL homolog on Daudi Burkitt's lymphoma cells. Fisch, P., Malkovsky, M., Kovats, S., Sturm, E., Braakman, E., Klein, B.S., Voss, S.D., Morrissey, L.W., DeMars, R., Welch, W.J. Science (1990) [Pubmed]
  2. Selection by two powerful antigens may account for the presence of the major population of human peripheral gamma/delta T cells. De Libero, G., Casorati, G., Giachino, C., Carbonara, C., Migone, N., Matzinger, P., Lanzavecchia, A. J. Exp. Med. (1991) [Pubmed]
  3. Rearrangement of variable region T cell receptor gamma genes in acute lymphoblastic leukemia. V gamma gene usage differs in mature and immature T cells. Hara, J., Benedict, S.H., Yumura, K., Ha-Kawa, K., Gelfand, E.W. J. Clin. Invest. (1989) [Pubmed]
  4. Predominant activation and expansion of V gamma 9-bearing gamma delta T cells in vivo as well as in vitro in Salmonella infection. Hara, T., Mizuno, Y., Takaki, K., Takada, H., Akeda, H., Aoki, T., Nagata, M., Ueda, K., Matsuzaki, G., Yoshikai, Y. J. Clin. Invest. (1992) [Pubmed]
  5. Usage of gamma chain variable regions in human acute lymphoblastic leukemias. González-Sarmiento, R., Greenberg, J.M., Kersey, J.H. Blood (1988) [Pubmed]
  6. Functional inactivation in the whole population of human V gamma 9/V delta 2 T lymphocytes induced by a nonpeptidic antagonist. Bürk, M.R., Carena, I., Donda, A., Mariani, F., Mori, L., De Libero, G. J. Exp. Med. (1997) [Pubmed]
  7. Molecular analysis of human gamma/delta+ clones from thymus and peripheral blood. Casorati, G., De Libero, G., Lanzavecchia, A., Migone, N. J. Exp. Med. (1989) [Pubmed]
  8. The human T-cell V gamma gene locus: cloning of new segments and study of V gamma rearrangements in neoplastic T and B cells. Chen, Z., Font, M.P., Loiseau, P., Bories, J.C., Degos, L., Lefranc, M.P., Sigaux, F. Blood (1988) [Pubmed]
  9. Prominent expansion of circulating lymphocytes bearing gamma T-cell receptors, with preferential expression of variable gamma genes after allogeneic bone marrow transplantation. Vilmer, E., Triebel, F., David, V., Rabian, C., Schumpp, M., Leca, G., Degos, L., Hercend, T., Sigaux, F., Bensussan, A. Blood (1988) [Pubmed]
  10. Phenotypical heterogeneity among human T cell receptor gamma/delta-expressing clones derived from peripheral blood. Koning, F., Knot, M., Wassenaar, F., Van den Elsen, P. Eur. J. Immunol. (1989) [Pubmed]
  11. The biased V gamma gene usage in the synovial fluid of patients with rheumatoid arthritis. Kageyama, Y., Koide, Y., Miyamoto, S., Inoue, T., Yoshida, T.O. Eur. J. Immunol. (1994) [Pubmed]
  12. Gene transfer studies of T cell receptor-gamma delta recognition. Specificity for staphylococcal enterotoxin A is conveyed by V gamma 9 alone. Loh, E.Y., Wang, M., Bartkowiak, J., Wiaderkiewicz, R., Hyjek, E., Wang, Z., Kozbor, D. J. Immunol. (1994) [Pubmed]
  13. Extrathymic origin of human gamma delta T cells during fetal development. McVay, L.D., Carding, S.R. J. Immunol. (1996) [Pubmed]
  14. MHC-unrestricted cytotoxic and proliferative responses of two distinct human gamma/delta T cell subsets to Daudi cells. Fisch, P., Oettel, K., Fudim, N., Surfus, J.E., Malkovsky, M., Sondel, P.M. J. Immunol. (1992) [Pubmed]
  15. Mycobacteria-reactive gamma delta T cells in HIV-infected individuals: lack of V gamma 9 cell responsiveness is due to deficiency of antigen-specific CD4 T helper type 1 cells. Wesch, D., Kabelitz, D., Friese, K., Pechhold, K. Eur. J. Immunol. (1996) [Pubmed]
  16. Cutting edge: human gamma delta T cells are activated by intermediates of the 2-C-methyl-D-erythritol 4-phosphate pathway of isoprenoid biosynthesis. Altincicek, B., Moll, J., Campos, N., Foerster, G., Beck, E., Hoeffler, J.F., Grosdemange-Billiard, C., Rodríguez-Concepción, M., Rohmer, M., Boronat, A., Eberl, M., Jomaa, H. J. Immunol. (2001) [Pubmed]
  17. Gamma delta T cells in rhesus monkeys and their response to simian immunodeficiency virus (SIV) infection. Gan, Y.H., Pauza, C.D., Malkovsky, M. Clin. Exp. Immunol. (1995) [Pubmed]
  18. Primary activation of V gamma 9-expressing gamma delta T cells by Mycobacterium tuberculosis. Requirement for Th1-type CD4 T cell help and inhibition by IL-10. Pechhold, K., Wesch, D., Schondelmaier, S., Kabelitz, D. J. Immunol. (1994) [Pubmed]
  19. Patterns of chemokine receptor expression on peripheral blood gamma delta T lymphocytes: strong expression of CCR5 is a selective feature of V delta 2/V gamma 9 gamma delta T cells. Glatzel, A., Wesch, D., Schiemann, F., Brandt, E., Janssen, O., Kabelitz, D. J. Immunol. (2002) [Pubmed]
  20. Production of interferon-gamma and tumour necrosis factor-alpha by human T-cell clones expressing different forms of the gamma delta receptor. Christmas, S.E., Meager, A. Immunology (1990) [Pubmed]
  21. Activation of human gamma delta T cells by Mycobacterium tuberculosis and Daudi lymphoma cells: differential regulatory effect of IL-10 and IL-12. Marx, S., Wesch, D., Kabelitz, D. J. Immunol. (1997) [Pubmed]
  22. Comparative analysis of alpha beta and gamma delta T cell activation by Mycobacterium tuberculosis and isopentenyl pyrophosphate. Wesch, D., Marx, S., Kabelitz, D. Eur. J. Immunol. (1997) [Pubmed]
  23. Clonal expansion of lymphocytes bearing the gamma delta T-cell receptor in a patient with large granular lymphocyte disorder. Vie, H., Chevalier, S., Garand, R., Moisan, J.P., Praloran, V., Devilder, M.C., Moreau, J.F., Soulillou, J.P. Blood (1989) [Pubmed]
  24. Synaptic transfer by human gamma delta T cells stimulated with soluble or cellular antigens. Espinosa, E., Tabiasco, J., Hudrisier, D., Fournié, J.J. J. Immunol. (2002) [Pubmed]
  25. The T cell receptors of human gamma delta T cells reactive to Mycobacterium tuberculosis are encoded by specific V genes but diverse V-J junctions. Ohmen, J.D., Barnes, P.F., Uyemura, K., Lu, S.Z., Grisso, C.L., Modlin, R.L. J. Immunol. (1991) [Pubmed]
  26. Polyclonal expansion of T-cell receptor-gamma delta+ T lymphocytes associated with neutropenia and thrombocytopenia. van Oostveen, J.W., Breit, T.M., de Wolf, J.T., Brandt, R.M., Smit, J.W., van Dongen, J.J., Borst, J., Melief, C.J. Leukemia (1992) [Pubmed]
 
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