A Keratinocyte-Responsive γδ TCR Is Necessary for Dendritic Epidermal T Cell Activation by Damaged Keratinocytes and Maintenance in the Epidermis

Jameson, Julie; Cauvi, Gabrielle; Witherden, Deborah A.; Havran, Wendy L.

doi:10.4049/jimmunol.172.6.3573

Cited by 130 publications

(163 citation statements)

References 32 publications

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“…Importantly, the use of Tcrd-H2BEGFP mice provided here for the first time a direct proof that the ''depleted'' gd T cells were actually still present. 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].…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…19,25,26 In the murine system, distinct subsets of cd T cells bearing specific pairs of the c and d TCR chains are targeted to particular epithelial locations during development such as the skin, lungs, uterus, vagina and tongue where they make up a significant portion of the local intraepithelial lymphocyte population and appear to respond to endogenous stress-induced antigens that have yet to be unambiguously identified. [27][28][29][30][31] For some of these special niche localized cd T…”

Section: Species Specificity: the Best Laid Plans Of Mice And Men Oftmentioning

confidence: 99%

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

2012

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The elusive task of defining the character of cd T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the a and b T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, cd T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and ab T cells are particularly well equipped to respond to the 'missing self' and the 'dangerous non-self', respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the 'safe non-self' and dealing with the inevitable 'distressed self', and it is within this more complex realm cd T cells excel thanks to their highly empathetic nature. This review gives an overview of the latest insights revealing the unfolding story of human cd T cells, providing a biographical sketch of these unique lymphocytes in an attempt to capture the essence of their fundamental nature and events that influence their life trajectory. What hangs in their balance is their nuanced ability to differentiate the friends from the foe and the pathological from the benign to help us adapt swiftly and efficiently to life's many stresses. Keywords: antigen recognition; danger-associated molecular patterns; gamma delta T cell subsets; immune homeostasis; innate immunity; stress response PROLOGUE Since the time of their accidental discovery during the molecular characterization of the a and b T cell receptor (TCR) genes belonging to their relatively unambiguous brethren, 1 'enigmatic' is still one of the most commonly used adjectives to describe cd T cells. This can be attributed to the fact that these unconventional lymphocytes have thus far been remarkably successful in thwarting most attempts at definition. Much of what we know about T cell biology and function comes from what has been discerned through studies done on ab T cells; however, one thing that is certain is that the majority of the rules governing the lives of ab T cells are surprisingly irrelevant when it comes to understanding the elusive character of cd T cells. Table 1 highlights some of the major differences between these two T cell subsets in humans.Recognition by cd T cells is not typically in the context of classical major histocompatibility complex (MHC) class I or II molecules and neither is antigen processing required. 2,3 These observations are corroborated by the fact that the majority of cd T cells are CD8 and CD4 negative. Crystal structure analysis of the cd TCR determined that the length and conformation of cd TCR resemble immunoglobulins (Ig) more than the ab TCR, which was taken to suggest that antigen recognition by cd T cells may be more similar to the binding of antibody to antigen rather than the MHC/peptide complex recognized by ab T cells. 4 The very basis of foreign antigen rec...

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“…Skin cd T cells were found to be critical in wound healing, [58][59][60][61][62] and IL-17 was reported to be elevated in patients with inflammatory skin diseases. 63 However, the role of IL-17 in cutaneous wound healing, and whether it is produced by skin cd T cells, are less clear.…”

Section: Function In Tissue Repair and Inflammationmentioning

confidence: 99%

Current progress in γδ T-cell biology

Hao

Xia

et al. 2010

Cell Mol Immunol

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T lymphocytes bearing c-and d-chain T-cell receptor heterodimers are named cd T cells. Interestingly, cd and ab T cells share the same progenitors, and they undergo a fate decision in the thymus. Functional differentiation of cd T cells occurs both inside and outside the thymus. Antigen recognition of cd T-cell receptors is very unique, and the responses frequently exhibit innate characteristics. Nevertheless, peripheral cd T cells exert a number of effector and regulatory functions. cd T cells rapidly produce cytokines like interferon (IFN)-c and IL-17 and promote inflammation, partly due to the inherent epigenetic and transcriptional programs, which facilitates a quick and extensive response. Moreover, cd T cells lyse target cells directly, and this is necessary for pathogen or tumor clearance. cd T cells can even serve as regulatory cells, and may contribute to immune suppression. Orchestration of cd T-cell and other immune cell interactions may be critical for host defense and immune regulation. Recently, cd T cells have been used for immunotherapy for infectious diseases and malignancy. In this review, we summarize the abstracts presented at the recent cd T cell Conference held from 19 to 21 May 2010, in Kiel, Germany (please see the website for details: http://www.gammadeltaconference.uni-kiel.de/index.html). Peptide-major histocompatibility complex-specific T-cell responses are known to be achieved by ab T cells, while cd T-cell biology is much less studied. Mice without cd T cells are highly susceptible to diseases and tumor, suggesting an important role of cd T cells in defense. By current technology in cellular and molecular immunology, researchers revealed that cd T cells produce a series of cytokines in pathology, and the effector cd T cells play an indispensable role in pathogen elimination, immune regulation and autoimmunity. As a group of innate immune cells, cd T cells respond rapidly and expand efficiently when stimulated by antigens or cytokines. cd T cells may be a good target for modulation of immune responses in human diseases. In recent years, a lot of researchers focused on the cd T-cell development, function and therapeutic use.

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A Keratinocyte-Responsive γδ TCR Is Necessary for Dendritic Epidermal T Cell Activation by Damaged Keratinocytes and Maintenance in the Epidermis

Cited by 130 publications

References 32 publications

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

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

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

Current progress in γδ T-cell biology

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