Pilarski L M, Miszta H, Turley E A
Department of Immunology, University of Alberta, Edmonton, Canada.
J Immunol. 1993 May 15;150(10):4292-302.
A receptor for hyaluronan-mediated motility (RHAMM) has been shown to promote cell locomotion. Among human T lineage lymphocytes, RHAMM is expressed only on a subset of thymocytes, being absent on mature peripheral T cells from blood, spleen, and lymph node. Among thymocytes, RHAMM is selectively expressed on a subset of CD3+ CD45RA+R0+ cells, and functions in motility as shown by the ability of anti-RHAMM to reduce the speed of thymocyte locomotion from 11 microns/minute to 3 microns/min. Although freshly isolated multi-negative (MN) thymocytes (CD3-4-8-19-) lack RHAMM, its expression is induced on day 3 of culture in a variety of conditions that support differentiation, as assessed by acquisition of CD3. When MN thymocytes are cultured on plates coated with fibronectin, expression of RHAMM is prolonged, but on uncoated surfaces, its expression is transient and lost by day 7 of culture with PHA or IL-2. Culture of MN thymocytes on thymic epithelial layers, with or without IL-2, resulted in a lack of RHAMM expression. Because in the absence of epithelial cells, RHAMM is expressed, the effect appears to be one of inhibition. Although expression of RHAMM by MN thymocytes cultured with IL-2 on uncoated surfaces is transient, addition of cyclosporin A resulted in prolonged expression. These observations are consistent with the view that cyclosporin A inactivates a RHAMM-directed inhibitory mechanism. Mature peripheral blood T cells transiently express RHAMM upon culture with PHA, PMA, or IL-2. T cells that expressed RHAMM after culture with PMA alone lacked RHAMM when stimulated by mitogenic CD2 antibodies with or without CD28 antibody, indicating inhibition of RHAMM expression. Thus expression of RHAMM is regulated by a RHAMM-directed inhibitory mechanism induced by stimulation through CD2/CD28. A similar mechanism may operate in thymocyte/epithelial cell cultures. These results suggest the inhibition of RHAMM during early, presumably sessile, thymic progenitor development, followed by its induction during developmental stages when locomotion is required. The apparently strong negative regulatory control over RHAMM expression by microenvironmental factors and by known thymic and T cell signaling molecules supports this view.
透明质酸介导的运动受体（RHAMM）已被证明可促进细胞运动。在人类T淋巴细胞系中，RHAMM仅在一部分胸腺细胞中表达，而在血液、脾脏和淋巴结中的成熟外周T细胞中不存在。在胸腺细胞中，RHAMM选择性地在CD3 + CD45RA + R0 +细胞亚群中表达，并具有运动功能，抗RHAMM能够将胸腺细胞运动速度从11微米/分钟降低到3微米/分钟就证明了这一点。虽然新鲜分离的多阴性（MN）胸腺细胞（CD3 - 4 - 8 - 19 -）缺乏RHAMM，但在支持分化的各种培养条件下，培养3天时其表达会被诱导，这可通过CD3的获得来评估。当MN胸腺细胞在包被有纤连蛋白的平板上培养时，RHAMM的表达会延长，但在未包被的表面上，其表达是短暂的，在PHA或IL - 2培养7天时会消失。MN胸腺细胞在胸腺上皮层上培养，无论有无IL - 2，都会导致RHAMM表达缺失。因为在没有上皮细胞时，RHAMM会表达，所以这种影响似乎是一种抑制作用。虽然在未包被表面上用IL - 2培养的MN胸腺细胞中RHAMM的表达是短暂的，但添加环孢素A会导致表达延长。这些观察结果与环孢素A使RHAMM定向抑制机制失活的观点一致。成熟外周血T细胞在用PHA、PMA或IL - 2培养时会短暂表达RHAMM。单独用PMA培养后表达RHAMM的T细胞在用有丝分裂原性CD2抗体（有无CD28抗体）刺激时缺乏RHAMM，表明RHAMM表达受到抑制。因此，RHAMM的表达受通过CD2/CD28刺激诱导的RHAMM定向抑制机制调控。类似的机制可能在胸腺细胞/上皮细胞培养中起作用。这些结果表明，在早期可能静止的胸腺祖细胞发育过程中RHAMM受到抑制，随后在需要运动的发育阶段被诱导。微环境因素以及已知的胸腺和T细胞信号分子对RHAMM表达的明显强大的负调控支持了这一观点。
