γδ T cell-induced nitric oxide production enhances resistance to mucosal candidiasis

Jones-Carson, Jessica; Vázquez‐Torres, Andrés; Heyde, Henri C. van der; Warner, Thomas F.; Wagner, R. Doug; Balish, Edward

doi:10.1038/nm0695-552

Cited by 120 publications

(78 citation statements)

References 42 publications

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“…[50][51][52][53][54][55][56] Furthermore, the key role of γδT cells in primary immune responses is undisputed in CMV, HSV-1 and Candida albicans infections, pathogens that are frequent after transplantation. [57][58][59] In addition, γδT cells are crucial modulators of immune responses and decisive in the induction and maintenance of tolerance in various physiological settings [60][61][62][63] and can directly promote allograft survival. 64 GZ-αβTCR was well tolerated, congruent with the bland cytokine signature obtained in vitro when crosslinking αβT cell TCR with GZ-αβTCR.…”

Section: Discussionmentioning

confidence: 99%

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

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Welker

Haarer

et al. 2014

Bone Marrow Transplant

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Allograft rejection and immunosuppression are two major issues in transplantation medicine. The specific targeting of alloreactive T cells, the initiators and promoters of allograft rejection, would be a promising strategy to reduce unwanted T-cell responses and side effects of lifelong immunosuppression. The novel humanized monoclonal antibody GZ-αβTCR, specific for the human αβT-cell receptor, was tested in vitro and in vivo for its specificity and efficacy to modulate the αβT-cell compartment. GZ-αβTCR moderately induced apoptosis in resting αβT cells in vitro, an effect considerably amplified in activated T cells. A single dose of GZ-αβTCR significantly reduced human CD45 + CD3 + T cells in vivo, with a preferential modulation of CD4 + αβT cells. Importantly, naive T cells, the T-cell subset from which alloreactivity emanates, were significantly reduced. Simultaneously, a significant, compensatory increase of γδ T cells was observed in vitro and in vivo in both humanized mouse models examined. GZ-αβTCR did not induce cytokines and was well tolerated. Thus, specificity and high efficacy make GZ-αβTCR a powerful tool to selectively eliminate putatively detrimental T-cell subsets, a major goal in transplantation medicine. At the same time, GZ-αβTCR spares γδ and natural killer cells, thus leaving the recipient's immune system competent for cell-mediated immunoregulation and cell-mediated immunity.

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Section: Discussionmentioning

confidence: 99%

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

Blank

Welker

Haarer

et al. 2014

Bone Marrow Transplant

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“…Most of these studies are related to infections such as Listeria monocytogenes, Salmonella choleraesuis, Mycobacterium tuberculosis, M. leprae, influenza virus, and Candida albicans (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). In these circumstances it is not always clear whether ␥␦ T cell Ag receptors are recognizing foreign Ags or interacting with self-ligands whose expression is induced by infection.…”

Section: Discussionmentioning

confidence: 99%

Infiltration of Canonical Vγ4/Vδ1 γδ T Cells in an Adriamycin-Induced Progressive Renal Failure Model

Ando

Watson

et al. 2001

The Journal of Immunology

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We have previously reported an infiltration of renal interstitial γδ T cells in Adriamycin-induced progressive glomerulosclerosis in the rat kidney. The TCR repertoire and sequences used by these γδ T cells have now been studied. Two injections of Adriamycin 14 days apart caused segmental glomerulosclerosis, massive interstitial infiltration of mononuclear cells, and end-stage renal failure. Flow cytometry of lymphocyte subpopulations with Abs to CD3, the γδ TCR, and the αβ TCR showed that γδ T cells as a proportion of CD3+ cells were increased in Adriamycin-treated kidneys (8.5 ± 5.4%), but not in lymph nodes (1.3 ± 0.4%). A semiquantitative score of glomerular damage (r = 0.65; p < 0.01) and creatinine (r = 0.62; p < 0.01) correlated significantly with the presence of γδ T cells. TCR Vγ repertoire analysis by RT-PCR and Southern blotting showed that Vγ2 was the dominant subfamily in lymph nodes, whereas Vγ4 became the predominant subfamily in advanced stages of the rat Adriamycin-treated kidney. Sequencing of the Vγ4-Jγ junctional region showed an invariant sequence. The amino acid sequence of the junctional region of the Vγ4 TCR was the same as the reported mouse canonical Vγ4 TCR sequence. Analysis of the kidney Vδ repertoire showed dominant expression of Vδ1, and sequencing again revealed the selective expression of a canonical Vδ1 gene. Semiquantitative RT-PCR for cytokine gene expression showed that γδ T cells from the kidneys expressed TGF-β, but not IL-4, IL-10, or IFN-γ. These results suggest that the predominant γδ T cells in the Adriamycin kidney use an invariant Vγ4/Vδ1 receptor.

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“…Several lines of evidence suggest that these cells play an important role in immunoregulation (37)(38)(39)(40)(41)(42)(43). ␥␦ T cells prime macrophages to produce TNF-␣ in response to LPS stimulation (43), and augment production of macrophage-derived NO (44). Depletion of ␥␦ T cells results in a decrease of TNF-␣, IL-1␤, IFN-␥, and IL-6 gene expression in the spinal cord of mice with autoimmune encephalomyelitis (45).…”

Section: Human V␥2v␦2 T Cells Augment Migration-inhibitory Factor Secmentioning

confidence: 99%

Human Vγ2Vδ2 T Cells Augment Migration-Inhibitory Factor Secretion and Counteract the Inhibitory Effect of Glucocorticoids on IL-1β and TNF-α Production

Wang

Das

Kamath

et al. 2002

The Journal of Immunology

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In immune cells, proinflammatory cytokine gene expression is regulated by glucocorticoids, whereas migration-inhibitory factor (MIF), a pleiotropic cytokine, has the unique property of counteracting the inhibitory effect of glucocorticoids on TNF-α and IL-1β secretion. A few lines of evidence suggest that γδ T cells play an important role in immunoregulation. However, it is unknown whether human γδ T cells participate in regulating MIF secretion, and how γδ T cells, glucocorticoids, and cytokines converge to give a unified physiological response. In this study, we demonstrate that human Vγ2Vδ2 T cells augment MIF secretion. Remarkably, these Vγ2Vδ2 T cells, functioning similarly to MIF in part, counteracted inhibition of dexamethasone on production of IL-1β and TNF-α. SCID mice reconstituted with human PBMC that were mock depleted of Vδ2 T cells and repeatedly infected with lethal dose of Escherichia coli had shorter survival time than those reconstituted with PBMC that were depleted of Vδ2 T cells. Thus, human Vγ2Vδ2 T cells are likely to play broad-spectrum roles in immunoregulation and immunopathology by influencing MIF secretion and the immunomodulatory function of glucocorticoids.

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γδ T cell-induced nitric oxide production enhances resistance to mucosal candidiasis

Cited by 120 publications

References 42 publications

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

Infiltration of Canonical Vγ4/Vδ1 γδ T Cells in an Adriamycin-Induced Progressive Renal Failure Model

Human Vγ2Vδ2 T Cells Augment Migration-Inhibitory Factor Secretion and Counteract the Inhibitory Effect of Glucocorticoids on IL-1β and TNF-α Production

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