Development of Dendritic Epidermal T Cells with a Skewed Diversity of γδTCRs in Vδ1-Deficient Mice

130

142

A unique population of T lymphocytes, designated dendritic epidermal T cells (DETC), homes to the murine epidermis during fetal development. DETC express a canonical γδ TCR, Vγ3/Vδ1, which recognizes Ag expressed on damaged, stressed, or transformed keratinocytes. Recently, DETC were shown to play a key role in the complex process of wound repair. To examine the role of the DETC TCR in DETC localization to the epidermis, maintenance in the skin, and activation in vivo, we analyzed DETC in the TCRδ−/− mouse. Unlike previous reports in which the TCRδ−/− skin was found to be devoid of any DETC, we discovered that TCRδ−/− mice have αβ TCR-expressing DETC with a polyclonal Vβ chain repertoire. The αβ DETC are not retained over the life of the animal, suggesting that the γδ TCR is critical for the maintenance of DETC in the skin. Although the αβ DETC can be activated in response to direct stimulation, they do not respond to keratinocyte damage. Our results suggest that a keratinocyte-responsive TCR is necessary for DETC activation in response to keratinocyte damage and for DETC maintenance in the epidermis.

supporting

confidence: 71%

mentioning

confidence: 97%

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

Jameson

Cauvi

Witherden

et al. 2004

130

142

“…V␦1-deficient mice were generated, as previously described (27). These mice were bred in specific pathogen-free conditions in our institute.…”

Section: Micementioning

confidence: 99%

Resident Vδ1+ γδ T Cells Control Early Infiltration of Neutrophils after Escherichia coli Infection via IL-17 Production

Shibata

Yamada

Hara

et al. 2007

Self Cite

441

410

Neutrophils infiltrate the site of infection and play critical roles in host defense, especially against extracellular bacteria. In the present study, we found a rapid and transient production of IL-17 after i.p. infection with Escherichia coli, preceding the influx of neutrophils. Neutralization of IL-17 resulted in a reduced infiltration of neutrophils and an impaired bacterial clearance. Ex vivo intracellular cytokine flow cytometric analysis revealed that γδ T cell population was the major source of IL-17. Mice depleted of γδ T cells by mAb treatment or mice genetically lacking Vδ1 showed diminished IL-17 production and reduced neutrophil infiltration after E. coli infection, indicating an importance of Vδ1+ γδ T cells as the source of IL-17. It was further revealed that γδ T cells in the peritoneal cavity of naive mice produced IL-17 in response to IL-23, which was induced rapidly after E. coli infection in a TLR4 signaling-dependent manner. Thus, although γδ T cells are generally regarded as a part of early induced immune responses, which bridge innate and adaptive immune responses, our study demonstrated a novel role of γδ T cells as a first line of host defense controlling neutrophil-mediated innate immune responses.

“…IL-17A KO (B6 background) mice were generated as described previously (12). The development of TCR Vd1 KO (13) and Vg4/6 KO (14) mice (B6 background) was reported previously. All animals were used for experiments at 8-12 wk of age.…”

Section: Micementioning

confidence: 99%

Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung

Yoshida

Umemura

Yahagi

et al. 2010

Self Cite

355

261

Granulomas play an essential role in the sequestration and killing of mycobacteria in the lung; however, the mechanisms of their development and maturation are still not clearly understood. IL-17A is involved in mature granuloma formation in the mycobacteria-infected lung. Therefore, IL-17A gene-knockout (KO) mice fail to develop mature granulomas in the Mycobacterium bovis bacille Calmette-Guérin (BCG)-infected lung. This study analyzed the mechanism of IL-17A–dependent mature granuloma formation in the mycobacteria-infected lung. The IL-17A KO mice showed a normal level of nascent granuloma formation on day 14 but failed to develop mature granulomas on day 28 after the BCG infection in the lung. The observation implies that IL-17A is required for the maturation of granuloma from the nascent to mature stage. TCR γδ T cells expressing TCR Vγ4 or Vγ6 were identified as the major IL-17A–producing cells that resided in the BCG-induced lung granuloma. The adoptive transfer of the IL-17A–producing TCR γδ T cells reconstituted granuloma formation in the IL-17A KO mice. The expression of ICAM-1 and LFA-1, which are adhesion molecules important in granuloma formation, decreased in the lung of the BCG-infected IL-17A KO mice, and their expression was induced on BCG-infected macrophages in coculture with IL-17A–producing TCR γδ T cells. Furthermore, IL-17A KO mice showed not only an impaired mature granuloma formation, but also an impaired protective response to virulent Mycobacterium tuberculosis. Therefore, IL-17A produced by TCR γδ T cells plays a critical role in the prevention of M. tuberculosis infection through the induction of mature granuloma formation.