Espinosa-Carrasco Gabriel, Le Saout Cécile, Fontanaud Pierre, Michau Aurélien, Mollard Patrice, Hernandez Javier, Schaeffer Marie
INSERM U1183, Institute for Regenerative Medicine and Biotherapy, University of Montpellier, Montpellier, France.
Institute of Functional Genomics, University of Montpellier, CNRS, INSERM, Montpellier, France.
Front Immunol. 2018 May 31;9:1156. doi: 10.3389/fimmu.2018.01156. eCollection 2018.
T cell search behavior is dictated by their need to encounter their specific antigen to eliminate target cells. However, mechanisms controlling effector T cell motility are highly tissue-dependent. Specifically, how diabetogenic T cells encounter their target beta cells in dispersed islets throughout the pancreas (PA) during autoimmune diabetes remains unclear. Using intra-vital 2-photon microscopy in a mouse model of diabetes, we found that CXCR3 chemokine downregulated CD8 T cell motility specifically within islets, promoting effector cell confinement to their target sites. By contrast, T cell velocity and directionality in the exocrine tissue were enhanced along blood vessels and extracellular matrix fibers. This guided migration implicated integrin-dependent interactions, since integrin blockade impaired exocrine T cell motility. In addition, integrin β1 blockade decreased CD4 T cell effector phenotype specifically in the PA. Thus, we unveil an important role for integrins in the PA during autoimmune diabetes that may have important implications for the design of new therapies.
T细胞的搜索行为取决于它们遇到特定抗原以消除靶细胞的需求。然而，控制效应T细胞运动的机制高度依赖于组织。具体而言，在自身免疫性糖尿病期间，致糖尿病T细胞如何在整个胰腺（PA）中分散的胰岛中遇到其靶标β细胞仍不清楚。我们在糖尿病小鼠模型中使用活体双光子显微镜发现，CXCR3趋化因子特异性下调胰岛内的CD8 T细胞运动，促进效应细胞局限于其靶位点。相比之下，外分泌组织中T细胞的速度和方向性沿血管和细胞外基质纤维增强。这种引导性迁移涉及整合素依赖性相互作用，因为整合素阻断会损害外分泌T细胞的运动。此外，整合素β1阻断特异性降低了PA中CD4 T细胞的效应表型。因此，我们揭示了整合素在自身免疫性糖尿病期间PA中的重要作用，这可能对新疗法的设计具有重要意义。
