Depletion of γδ T Cells Exacerbates Murine Adriamycin Nephropathy

Wu, Huiling; Wang, Yuan Min; Wang, Yiping; Hu, Min; Zhang, Geoff Yu; Knight, John; Harris, David C.H.; Alexander, Stephen I.

doi:10.1681/asn.2006060622

Cited by 51 publications

(56 citation statements)

References 43 publications

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“…In contrast, Wu et al reported that the depletion of gd T cells, using the anti-dTCR antibody UC7-13D5, exacerbates the course of adriamycin nephropathy, a murine model of human FSGS. 32 However, treatment with the UC7-13D5 antibody does not deplete gd T cells in vivo but rather leads to TCR internalization and thereby generates "invisible," but activated, gd T cells. 33 This might be a possible explanation for the controversial findings described above.…”

Section: Discussionmentioning

confidence: 99%

IL-17A Production by Renal γδ T Cells Promotes Kidney Injury in Crescentic GN

Turner¹,

Krebs²,

Tittel³

et al. 2012

Journal of the American Society of Nephrology

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The Th17 immune response appears to contribute to the pathogenesis of human and experimental crescentic GN, but the cell types that produce IL-17A in the kidney, the mechanisms involved in its induction, and the IL-17A-mediated effector functions that promote renal tissue injury are incompletely understood. Here, using a murine model of crescentic GN, we found that CD4 + T cells, gd T cells, and a population of CD3 + CD4 2 CD8 2 gdT cell receptor 2 NK1.1 2 T cells all produce IL-17A in the kidney. A time course analysis identified gd T cells as a major source of IL-17A in the early phase of disease, before the first CD4 + Th17 cells arrived. The production of IL-17A by renal gd T cells depended on IL-23p19 signaling and retinoic acid-related orphan receptor-gt but not on IL-1b or IL-6. In addition, depletion of dendritic cells, which produce IL-23 in the kidney, reduced IL-17A production by renal gd T cells. Furthermore, the lack of IL-17A production in gd T cells, as well as the absence of all gd T cells, reduced neutrophil recruitment into the kidney and ameliorated renal injury. Taken together, these data suggest that gd T cells produce IL-17A in the kidney, induced by IL-23, promoting neutrophil recruitment, and contributing to the immunopathogenesis of crescentic GN.

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Section: Discussionmentioning

confidence: 99%

IL-17A Production by Renal γδ T Cells Promotes Kidney Injury in Crescentic GN

Turner¹,

Krebs²,

Tittel³

et al. 2012

Journal of the American Society of Nephrology

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“…56 All glomeruli per section were scored to determine the percentage of glomeruli displaying glomerulosclerosis.…”

Section: Histologymentioning

confidence: 99%

Absence of MyD88 Signaling Induces Donor-Specific Kidney Allograft Tolerance

Noordmans

O'Brien

et al. 2012

Journal of the American Society of Nephrology

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Toll-like receptors (TLRs) play a fundamental role in innate immunity and provide a link between innate and adaptive responses to an allograft; however, whether the development of acute and chronic allograft rejection requires TLR signaling is unknown. Here, we studied TLR signaling in a fully MHC-mismatched, life-sustaining murine model of kidney allograft rejection. Mice deficient in the TLR adaptor protein MyD88 developed donor antigen-specific tolerance, which protected them from both acute and chronic allograft rejection and increased their survival after transplantation compared with wild-type controls. Administration of an anti-CD25 antibody to MyD88-deficient recipients depleted CD4 + CD25 + FoxP3 + cells and broke tolerance. In addition, defective development of Th17 immune responses to alloantigen both in vitro and in vivo occurred, resulting in an increased ratio of Tregs to Th17 effectors. Thus, MyD88 deficiency was associated with an altered balance of Tregs over Th17 cells, promoting tolerance instead of rejection. This study provides evidence that targeting innate immunity may be a clinically relevant strategy to facilitate transplantation tolerance.

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“…To our knowledge, four different ''classical'' mAb To date, these mAb have been used for gd T-cell depletion with varying success. Although the depletion-capacity of GL3 has been disputed repeatedly [13,14], many groups continue to use gd T-cell depletion protocols involving UC7-13D5 [15][16][17][18][19]. In most of the published studies, effective gd T-cell depletion with UC7-13D5 was confirmed by surface staining using conjugated GL3 mAb.…”

mentioning

confidence: 99%

“…This is a particular pity, since gd T-cell depletion avoids the limitations of the Tcrd knock-out model in which opportunistic ab T cells can occupy gd T-cell niches and may partially substitute the functions of genuine gd T cells [9]. Nevertheless, many recent studies found interesting effects after administration of anti-gd TCR mAb, mainly using the UC7-13D5 hybridoma [15][16][17][18][19]. Moreover, several studies found opposing effects of gd T-cell depletion and adoptive transfer of gd T cells [17,22] as well as similar experimental outcomes in Tcrd -/-and gd T-cell-depleted mice [17,23], strongly suggesting functional relevance of the mAb administration.…”

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confidence: 99%

In vivo application of mAb directed against the γδ TCR does not deplete but generates “invisible” γδ T cells

et al. 2009

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mAb targeting the cd TCR have been used for cd T-cell depletion with varying success. Although the depletion-capacity of the anti-cd TCR mAb clone GL3 has been disputed repeatedly, many groups continue to use cd T-cell depletion protocols involving the mAb clone UC7-13D5 and find significant biological effects. We show here that treatment with both GL3 and UC7-13D5 antibodies does not deplete cd T cells in vivo, but rather leads to TCR internalization and thereby generates ''invisible'' cd T cells. We addressed this issue using anti-cd TCR mAb injections into WT mice as well as into reporter TCR delta locushistone 2B enhanced GFP knock-in mice, in which cd T cells can be detected based on an intrinsic green fluorescence. Importantly, the use of TCR delta locus-histone 2B enhanced GFP mice provided here for the first time direct evidence that the ''depleted'' cd T cells were actually still present. Our results show further that GL3 and UC7-13D5 mAb are in part cross-competing for the same epitope. Assessed by activation markers, we observed in vitro and in vivo activation of cd T cells through mAb. We conclude that cd T-cell depletion experiments must be evaluated with caution and discuss the implications for future studies on the physiological functions of cd T cells.Key words: cd T cells . gd T-cell depletion . mAb TCR delta locus-histone 2BeGFP reporter mice Introduction gd T cells constitute a distinct lineage of T lymphocytes. Many T cells reside in mucosal tissues in close contact with epithelial cells. There, they often represent the majority of the T-cell pool and have tissue-specific oligoclonal TCR repertoires. Circulating gd T cells show a more diverse TCR repertoire, but make up only 0.5-3% of all T cells in the blood and in secondary lymphoid organs such as lymph nodes and spleen. Both mucosal and circulating gd T cells seem to play specific roles in the regulation and execution of host responses to many pathogens [1][2][3].Recently, gd T cells have received an increasing attention as main producers of the pro-inflammatory cytokine IL17A [4][5][6][7]. In contrast to the progress made in understanding their counterparts of the ab T-cell lineage, the biological role of gd T cells is only slowly emerging. Research on gd T cells must cope with various obstacles: (i) currently, information on gd TCR ligands is still very limited; (ii) in the mouse model and in the human system there is no other gd T-cell specific marker than the gd TCR itself; and (iii) the functional phenotype of TCR delta locus (Tcrd)-deficient (Tcrd -/-) mice [8] may be concealed by opportunistic ab T cells that occupy the niches of genuine gd T cells and might partially take over their functions [9]. However, a popular approach to overcome the latter issue is to deplete gd T cells in WT mice with mAb directed against gd TCR instead of using the Tcrd -/-model. To our knowledge, four different ''classical'' mAb To date, these mAb have been used for gd T-cell depletion with varying success. Although the depletion-capacity of GL3 has been...

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Depletion of γδ T Cells Exacerbates Murine Adriamycin Nephropathy

Cited by 51 publications

References 43 publications

IL-17A Production by Renal γδ T Cells Promotes Kidney Injury in Crescentic GN

IL-17A Production by Renal γδ T Cells Promotes Kidney Injury in Crescentic GN

Absence of MyD88 Signaling Induces Donor-Specific Kidney Allograft Tolerance

In vivo application of mAb directed against the γδ TCR does not deplete but generates “invisible” γδ T cells

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