Crotzer Victoria L, Mabardy Allan S, Weiss Arthur, Brodsky Frances M
The GW Hooper Foundation, Department of Microbiology, University of California San Francisco, 94143, USA.
J Exp Med. 2004 Apr 5;199(7):981-91. doi: 10.1084/jem.20031105.
T cell receptor (TCR) internalization by clathrin-coated vesicles after encounter with antigen has been implicated in the regulation of T cell responses. We demonstrate that TCR internalization after receptor engagement and TCR signaling involves inducible phosphorylation of clathrin heavy chain (CHC) in both CD4+ and CD8+ human T cells. Studies with mutant Jurkat T cells implicate the Src family kinase Lck as the responsible enzyme and its activity in this process is influenced by the functional integrity of the downstream signaling molecule ZAP-70. CHC phosphorylation positively correlates with ligand-induced TCR internalization in both CD4+ and CD8+ T cells, and CHC phosphorylation as a result of basal Lck activity is also implicated in constitutive TCR endocytosis by CD4+ T cells. Remarkably, irreversible CHC phosphorylation in the presence of pervanadate reduced both constitutive and ligand-induced TCR internalization in CD4+ T cells, and immunofluorescence studies revealed that this inhibition affected the early stages of TCR endocytosis from the plasma membrane. Thus, we propose that CHC phosphorylation and dephosphorylation are involved in TCR internalization and that this is a regulatory mechanism linking TCR signaling to endocytosis.
T细胞受体（TCR）在与抗原相遇后通过网格蛋白包被的囊泡进行内化，这与T细胞反应的调节有关。我们证明，受体结合和TCR信号传导后TCR的内化涉及CD4⁺和CD8⁺人T细胞中网格蛋白重链（CHC）的诱导性磷酸化。对突变型Jurkat T细胞的研究表明，Src家族激酶Lck是负责的酶，其在这一过程中的活性受下游信号分子ZAP-70功能完整性的影响。CHC磷酸化与配体诱导的CD4⁺和CD8⁺ T细胞中TCR的内化呈正相关，并且基础Lck活性导致的CHC磷酸化也与CD4⁺ T细胞组成型TCR内吞作用有关。值得注意的是，在过氧钒酸盐存在下不可逆的CHC磷酸化降低了CD4⁺ T细胞中组成型和配体诱导的TCR内化，免疫荧光研究表明这种抑制作用影响了TCR从质膜内吞的早期阶段。因此，我们提出CHC的磷酸化和去磷酸化参与了TCR的内化，并且这是一种将TCR信号传导与内吞作用联系起来的调节机制。
