Rennert P D, Browning J L, Mebius R, Mackay F, Hochman P S
Biogen Inc., Cambridge, Massachusetts 02142, USA.
J Exp Med. 1996 Nov 1;184(5):1999-2006. doi: 10.1084/jem.184.5.1999.
For more than a decade, the biological roles and the apparent redundancy of the cytokines tumor necrosis factor (TNF) and lymphotoxin (LT) have been debated. LT alpha exists in its soluble form as a homotrimer, which like TNF only binds the TNF receptors, TNF-R55 or TNF-R75. The cell surface form of LT exists as a heteromer of LT alpha and LT beta subunits and this complex specifically binds the LT beta receptor (LT beta-R). To discriminate the functions of the LT and TNF systems, soluble LT beta-R-immunoglobulin (Ig) or TNF-R-Ig fusion proteins were introduced into embryonic circulation by injecting pregnant mice. Exposure to LT beta-R-Ig during gestation disrupted lymph node development and splenic architecture in the progeny indicating that both effects are mediated by the surface LT alpha/beta complex. These data are the first to identify a cell surface ligand involved in immune organ morphogenesis. Moreover, they unambiguously discriminate the functions of the various TNF/LT ligands, provide a unique model to study compartmentalization of immune responses and illustrate the generic utility of receptor-Ig fusion proteins for dissecting/ordering ontogenetic events in the absence of genetic modifications.
十多年来，细胞因子肿瘤坏死因子（TNF）和淋巴毒素（LT）的生物学作用及其明显的冗余性一直存在争议。LTα以可溶性同三聚体形式存在，它与TNF一样，仅与TNF受体TNF-R55或TNF-R75结合。LT的细胞表面形式以LTα和LTβ亚基的异源二聚体存在，这种复合物特异性地结合LTβ受体（LTβ-R）。为了区分LT和TNF系统的功能，通过注射怀孕小鼠将可溶性LTβ-R免疫球蛋白（Ig）或TNF-R-Ig融合蛋白引入胚胎循环。孕期接触LTβ-R-Ig会破坏子代的淋巴结发育和脾脏结构，表明这两种效应均由表面LTα/β复合物介导。这些数据首次确定了一种参与免疫器官形态发生的细胞表面配体。此外，它们明确区分了各种TNF/LT配体的功能，提供了一个研究免疫反应区室化的独特模型，并说明了受体-Ig融合蛋白在无需基因修饰的情况下剖析/梳理个体发育事件的一般用途。
