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  • 1
    Online Resource
    Online Resource
    Interleukin‐23–Dependent γ/δ T Cells Produce Interleukin‐17 and Accumulate in the Enthesis, Aortic Valve, and Ciliary Body in Mice
    Wiley ; 2016
    In:  Arthritis & Rheumatology Vol. 68, No. 10 ( 2016-10), p. 2476-2486
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 68, No. 10 ( 2016-10), p. 2476-2486
    Abstract: The spondyloarthritides (SpA) are a group of rheumatic diseases characterized by ossification and inflammation of entheseal tissue, the region where tendon attaches to bone. Interleukin‐23 (IL‐23) is involved in the pathogenesis of SpA by acting on IL‐23 receptor (IL‐23R) expressed on enthesis‐resident lymphocytes. Upon IL‐23 binding, CD3+CD4−CD8− tissue‐resident lymphocytes secrete IL‐17A and IL‐22, leading to inflammation, bone loss, and ossification. Knowledge about enthesis‐resident lymphocytes remains fragmentary, and the contribution of entheseal γ/δ T cells in particular is not clear. This study was undertaken to investigate the presence of γ/δ T cells in the enthesis. Methods We used 2‐photon microscopy and flow cytometry to analyze entheseal lymphocytes from C57BL/6, Tcrd‐H2BeGFP , Rorc‐GFP , and IL‐23R‐eGFP mice. To analyze entheseal γ/δ T cells in IL‐23−induced inflammation, Tcrd‐H2BeGFP mice were crossed with mice of the susceptible B10.RIII background. Hydrodynamic injection of IL‐23 minicircle DNA was performed for overexpression of IL‐23 and induction of inflammation. Light‐sheet fluorescence microscopy was used to visualize arthritic inflammation. Results Activated Vγ6+CD27− γ/δ T cells were abundant in uninflamed entheseal tissue and constituted the large majority of retinoic acid receptor−related orphan nuclear receptor γt (RORγt)+IL‐23R+ enthesis‐resident lymphocytes. Fetal thymus−dependent γ/δ T cells were the main source of IL‐17A at the enthesis. Under inflammatory conditions, γ/δ T cells increased in number at the Achilles tendon enthesis, aortic root, and adjacent to the ciliary body. Conclusion Entheseal γ/δ T cells are derived from fetal thymus and are maintained as self‐renewing tissue‐resident cells. As main IL‐17A producers within tissues exposed to mechanical stress including enthesis, γ/δ T cells are key players in the pathogenesis of IL‐23−induced local inflammation.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v68.10
    DOI: 10.1002/art.39732
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2754614-7
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  • 2
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    Online Resource
    Disruption of de novo fatty acid synthesis via acetyl‐CoA carboxylase 1 inhibition prevents acute graft‐versus‐host disease
    Wiley ; 2016
    In:  European Journal of Immunology Vol. 46, No. 9 ( 2016-09), p. 2233-2238
    Details
    In: European Journal of Immunology, Wiley, Vol. 46, No. 9 ( 2016-09), p. 2233-2238
    Abstract: Upon antigen‐specific or allogeneic activation, T cells sharply increase their metabolic activity to cope with augmented needs for proliferation and effector functions. Therefore, enzymes involved in energy metabolism constitute attractive targets to modulate the activity of pathogenic effector T cells in the setting of graft‐versus‐host‐disease (GVHD). Here, we show that T cells deficient for acetyl‐CoA carboxylase 1 (TACC1) are dramatically less pathogenic than wild‐type (WT) T cells in a lethal C57BL/6 into BALB/c model of acute GVHD and permitted sustained survival of recipient mice. In line with this clinical observation, higher frequencies of GVHD‐suppressing Foxp3 + regulatory T (Treg) cells were detected in the colon of TACC T‐cell recipients. In vitro, T‐cell stimulation with allogeneic DCs induced higher proportions of Treg cells but also led to diminished proliferation of TACC1 T cells compared to WT T cells. Furthermore, TACC1 T cells activated by allogeneic DCs showed impaired glycolysis and lipid synthesis. Thus, targeting de novo fatty acid synthesis via acetyl‐CoA carboxylase inhibition may be a promising new strategy to prevent GVHD.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Issue
    URL: Article
    DOI: 10.1002/eji.v46.9
    DOI: 10.1002/eji.201546152
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 1491907-2
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  • 3
    Online Resource
    Online Resource
    CCR7‐mediated migration in the thymus controls γδ T‐cell development
    Wiley ; 2014
    In:  European Journal of Immunology Vol. 44, No. 5 ( 2014-05), p. 1320-1329
    Details
    In: European Journal of Immunology, Wiley, Vol. 44, No. 5 ( 2014-05), p. 1320-1329
    Abstract: αβ T‐cell development and selection proceed while thymocytes successively migrate through distinct regions of the thymus. For γδ T cells, the interplay of intrathymic migration and cell differentiation is less well understood. Here, we crossed C‐C chemokine receptor (CCR)7‐deficient ( Ccr7 −/− ) and CCR9‐deficient mice ( Ccr9 −/− ) to mice with a TcrdH2BeGFP reporter background to investigate the impact of thymic localization on γδ T‐cell development. γδ T‐cell frequencies and numbers were decreased in CCR7‐deficient and increased in CCR9‐deficient mice. Transfer of CCR7‐ or CCR9‐deficient BM into irradiated C57BL/6 WT recipients reproduced these phenotypes, pointing toward cell‐intrinsic migration defects. Monitoring recent thymic emigrants by intrathymic labeling allowed us to identify decreased thymic γδ T‐cell output in CCR7‐deficient mice. In vitro, CCR7‐deficient precursors showed normal γδ T‐cell development. Immunohistology revealed that CCR7 and CCR9 expression was important for γδ T‐cell localization within thymic medulla or cortex, respectively. However, γδ T‐cell motility was unaltered in CCR7‐ or CCR9‐deficient thymi. Together, our results suggest that proper intrathymic localization is important for normal γδ T‐cell development.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Issue
    URL: Article
    DOI: 10.1002/eji.v44.5
    DOI: 10.1002/eji.201344330
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 1491907-2
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  • 4
    Online Resource
    Online Resource
    Eomes expression reports the progressive differentiation of IFN‐γ‐producing Th1‐like γδ T cells
    Wiley ; 2017
    In:  European Journal of Immunology Vol. 47, No. 6 ( 2017-06), p. 970-981
    Details
    In: European Journal of Immunology, Wiley, Vol. 47, No. 6 ( 2017-06), p. 970-981
    Abstract: The transcription factor Eomesodermin (Eomes) plays a crucial role in regulating cytotoxic function, development, and survival of immune cells. γδ T cells can express Eomes, but its contribution to their differentiation is unknown. Using Eomes‐IRES‐GFP mice, we show that Eomes + γδ T cells are unequally distributed among organs, with the highest proportion in spleen. While the majority of Eomes + γδ T cells expressed Vγ1 + and Vγ4 + TCRs, Eomes was absent in Vγ5 + , Vγ6 + , and Vγ7 + subsets. Moreover, Eomes was co‐expressed in γδ T cells with Th1 lineage‐related factors such as CD27, T‐bet, and Ly6C, but not with Th17 lineage‐related genes. Eomes + and Eomes ‒ γδ T‐cell populations showed distinct gene expression profiles, with an increase of cytotoxic‐related genes in Eomes + γδ T cells. Furthermore, Eomes could be induced in peripheral γδ T cells by IL‐12 and IL‐4, and Eomes + γδ T cells presented a higher proliferation rate and IFN‐γ production when stimulated in vitro with IL‐12 and IL‐18. However, γδ T cells with very high Eomes levels displayed an exhausted phenotype with high levels of PD‐1, and were less capable of IFN‐γ production. Together, this study highlights Eomes as a marker for the differentiation of Th1‐like effector γδ T cells.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Issue
    URL: Article
    DOI: 10.1002/eji.v47.6
    DOI: 10.1002/eji.201646753
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 1491907-2
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