Ocana-Morgner Carlos, Wahren Christine, Jessberger Rolf
Institute of Physiological Chemistry, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
Blood. 2009 Feb 12;113(7):1474-82. doi: 10.1182/blood-2008-04-152587. Epub 2008 Sep 18.
Stimulated dendritic cells (DCs) mature and migrate to lymphoid organs to prime naive T cells. DC maturation augments antigen-presentation capacity of DCs by increasing peptide loading, half-life, and cell surface localization of MHC molecules. Activated SWAP-70(-/-) DCs fail to properly localize MHCII molecules in the plasma membrane, are strongly impaired in T-cell activation, and are altered in F-actin rearrangement. MHCII synthesis, invariant chain removal, and MHCII internalization, however, are unaffected. MHCII surface localization is known to require RhoGTPases. Surprisingly, SWAP70, hitherto known to bind F-actin and Rac, also binds RhoA-GTP. In SWAP-70(-/-) DCs, RhoA and RhoB are stimulus-independent and constitutively active. Surface localization of MHCII molecules and T-cell activation can be restored by blocking RhoA and RhoB before but not during DC activation. Thus, contrasting positive regulation of Rac, SWAP-70 negatively regulates RhoA and-indirectly-RhoB, preventing premature RhoA/RhoB activation. Through RhoA/RhoB regulation, SWAP-70 defines a new pathway to control surface localization of MHCII, a critical element in DC-dependent immune responses.
受刺激的树突状细胞（DCs）成熟并迁移至淋巴器官以激活初始T细胞。DC成熟通过增加肽负载、半衰期以及MHC分子的细胞表面定位来增强DC的抗原呈递能力。活化的SWAP - 70（-/-）DC无法将MHCII分子正确定位在质膜中，在T细胞活化方面严重受损，并且F - 肌动蛋白重排发生改变。然而，MHCII合成、恒定链去除以及MHCII内化不受影响。已知MHCII表面定位需要RhoGTPases。令人惊讶的是，迄今已知与F - 肌动蛋白和Rac结合的SWAP70也与RhoA - GTP结合。在SWAP - 70（-/-）DC中，RhoA和RhoB不依赖刺激且组成性激活。在DC激活之前而非激活期间阻断RhoA和RhoB可恢复MHCII分子的表面定位和T细胞活化。因此，与Rac的正向调节相反，SWAP - 70负向调节RhoA以及间接调节RhoB，防止RhoA/RhoB过早激活。通过RhoA/RhoB调节，SWAP - 70定义了一条控制MHCII表面定位的新途径，这是DC依赖性免疫反应中的关键要素。
