Marschner S, Freiberg B A, Kupfer A, Hünig T, Finkel T H
Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9763-8. doi: 10.1073/pnas.96.17.9763.
Lymphocyte circulation plays an important role in the generation of a specific immune response. Mature lymphocytes continuously circulate between blood and lymph, entering the lymphoid tissue via high endothelial venules. Trafficking across high endothelial venules of peripheral lymph nodes (PLN) depends on the expression of L-selectin. It has been shown that L-selectin is rapidly cleaved from the surface by a metalloproteinase after in vitro activation. Here, we show that ligation of CD4, without ligation of the T cell receptor for antigen, causes down-regulation of L-selectin on T helper cells. This down-regulation is caused by proteolytic cleavage by a metalloproteinase and is reversible by the addition of hydroxamic acid-based metalloproteinase inhibitors. We show that in vivo down-regulation of L-selectin in huCD4tg mice by mAb reduces the homing of lymphocytes to PLN in adoptive transfer experiments. Because CD4 is a coreceptor for HIV-1, the down-regulation of L-selectin induced by CD4 ligation could play a role in the pathogenesis of AIDS. We provide evidence that CD4 ligation by HIV-1 induces metalloproteinase-dependent L-selectin down-regulation. Reduced levels of L-selectin expression might contribute to immune deficiency in individuals infected with HIV by inhibiting T cell redistribution and decreasing the probability of an encounter between specific lymphocytes and viral antigens in PLN.
淋巴细胞循环在特异性免疫反应的产生中起着重要作用。成熟淋巴细胞在血液和淋巴之间持续循环，通过高内皮微静脉进入淋巴组织。穿越外周淋巴结（PLN）高内皮微静脉的迁移取决于L-选择素的表达。研究表明，体外激活后，L-选择素会被金属蛋白酶迅速从细胞表面切割下来。在此，我们发现，在不连接抗原T细胞受体的情况下，CD4的连接会导致辅助性T细胞上L-选择素的下调。这种下调是由金属蛋白酶的蛋白水解切割引起的，添加基于异羟肟酸的金属蛋白酶抑制剂可使其逆转。我们表明，在过继转移实验中，单克隆抗体导致huCD4tg小鼠体内L-选择素下调，减少了淋巴细胞归巢至PLN。由于CD4是HIV-1的共受体，CD4连接诱导的L-选择素下调可能在艾滋病发病机制中起作用。我们提供证据表明，HIV-1介导的CD4连接诱导金属蛋白酶依赖性L-选择素下调。L-选择素表达水平降低可能通过抑制T细胞重新分布以及降低PLN中特定淋巴细胞与病毒抗原相遇的概率，导致HIV感染者的免疫缺陷。
