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

• Southern blot analysis showed preferential rearrangements of the V gamma 9 genes [23].
• Northern blot demonstrated the presence of V gamma 9 mRNA transcripts [23].
• Using flow cytometry and confocal microscopy, we show in this work that Ag-stimulated human V gamma 9/V delta 2 T cells conjugate to, and perform molecular transfer from, various tumor cell targets [24].
• Molecular analysis by PCR amplification confirmed use of the V delta 2 and V gamma 9 gene segments in these cells, and demonstrated predominant usage of J delta 1 and J gamma P gene segments [25].
• Immunofluorescence (IF) stainings with subset-specific monoclonal antibodies showed a fluctuating expansion of TcR-gamma delta+ T-cells expressing V gamma 9 and V delta 2 variable (V) gene segments [26].

References