Danzer Claudia, Koller Anna, Baier Julia, Arnold Harald, Giessler Claudia, Opoka Robert, Schmidt Stephanie, Willers Maike, Mihai Sidonia, Parsch Hans, Wirtz Stefan, Daniel Christoph, Reinhold Annegret, Engelmann Swen, Kliche Stefanie, Bogdan Christian, Hoebe Kasper, Mattner Jochen
Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
Eur J Immunol. 2016 Sep;46(9):2121-36. doi: 10.1002/eji.201646331. Epub 2016 Jul 29.
TCR ligation is critical for the selection, activation, and integrin expression of T lymphocytes. Here, we explored the role of the TCR adaptor protein slp-76 on iNKT-cell biology. Compared to B6 controls, slp-76(ace/ace) mice carrying a missense mutation (Thr428Ile) within the SH2-domain of slp-76 showed an increase in iNKT cells in the thymus and lymph nodes, but a decrease in iNKT cells in spleens and livers, along with reduced ADAP expression and cytokine response. A comparable reduction in iNKT cells was observed in the livers and spleens of ADAP-deficient mice. Like ADAP(-/-) iNKT cells, slp-76(ace/ace) iNKT cells were characterized by enhanced CD11b expression, correlating with an impaired induction of the TCR immediate-early gene Nur77 and a decreased adhesion to ICAM-1. Furthermore, CD11b-intrinsic effects inhibited cytokine release, concanavalin A-mediated inflammation, and iNKT-cell accumulation in the liver. Unlike B6 and ADAP(-/-) mice, the expression of the transcription factors Id3 and PLZF was reduced, whereas NP-1-expression was enhanced in slp-76(ace/ace) mice. Blockade of NP-1 decreased the recovery of iNKT cells from peripheral lymph nodes, identifying NP-1 as an iNKT-cell-specific adhesion factor. Thus, slp-76 contributes to the regulation of the tissue distribution, PLZF, and cytokine expression of iNKT cells via ADAP-dependent and -independent mechanisms.
TCR连接对于T淋巴细胞的选择、激活和整合素表达至关重要。在此，我们探究了TCR衔接蛋白slp-76在iNKT细胞生物学中的作用。与B6对照相比，在slp-76的SH2结构域内携带错义突变（Thr428Ile）的slp-76(ace/ace)小鼠胸腺和淋巴结中的iNKT细胞增加，但脾脏和肝脏中的iNKT细胞减少，同时ADAP表达和细胞因子反应降低。在ADAP缺陷小鼠的肝脏和脾脏中观察到iNKT细胞有类似程度的减少。与ADAP(-/-) iNKT细胞一样，slp-76(ace/ace) iNKT细胞的特征是CD11b表达增强，这与TCR立即早期基因Nur77诱导受损以及对ICAM-1的粘附减少相关。此外，CD11b内在效应抑制细胞因子释放、伴刀豆球蛋白A介导的炎症以及肝脏中iNKT细胞的积累。与B6和ADAP(-/-)小鼠不同，转录因子Id3和PLZF的表达在slp-76(ace/ace)小鼠中降低，而NP-1表达增强。阻断NP-1可减少外周淋巴结中iNKT细胞的恢复，确定NP-1为iNKT细胞特异性粘附因子。因此，slp-76通过依赖ADAP和不依赖ADAP的机制参与iNKT细胞的组织分布、PLZF和细胞因子表达的调节。
