Tumanov Alexei V, Grivennikov Sergei I, Shakhov Alexander N, Rybtsov Stanislav A, Koroleva Ekaterina P, Takeda Junji, Nedospasov Sergei A, Kuprash Dmitry V
Laboratory of Molecular Immunology,Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
Immunol Rev. 2003 Oct;195:106-16. doi: 10.1034/j.1600-065x.2003.00071.x.
Mice with inactivation of lymphotoxin beta receptor (LTbetaR) system have profound defects in the development and maintenance of peripheral lymphoid organs. As surface LT is expressed by lymphocytes, natural killer cells, and lymphoid tissue-initiating cells as well as by some other cell types, we dissected cell type-specific LT contribution into the complex LT-deficient phenotype by conditional gene targeting. B-LTbeta knockout (KO) mice displayed an intermediate phenotype in spleen as compared with mice with complete LTbeta deficiency. In contrast, T-LTbeta KO mice displayed normal structure of the spleen. However, inactivation of LTbeta in both T and B cells resulted in additional defects in the structure of the marginal zone and in the development of follicular dendritic cells in spleen. Structure of lymph nodes (LN) and Peyer's patches (PP) was normal in both B-LTbeta KO and T- and B-LTbeta KO mice, except that PPs were of reduced size. When compared across the panel of lymphocyte-specific LT KOs, the defects in antibody responses to T-cell-dependent antigens correlated with the severity of defects in spleen structure. Expression of CCL21 and CCL19 chemokines was not affected in spleen, LN and PP of B-LTbeta KO and T- and B-LTbeta KO mice, while CXCL13 was slightly reduced only in spleen. Collectively, our data suggest the following: (i). requirements for LT signaling to support architecture of spleen, LN and PP are different; (ii). LT complex expressed by B cells plays a major role in the maintenance of spleen structure, while surface LT expressed by T cells provides a complementary but distinct signal; and (iii). in a non-transgenic model, expression of lymphoid tissue chemokines is only minimally dependent on the expression of surface LT complex on B and T lymphocytes.
淋巴毒素β受体（LTβR）系统失活的小鼠在外周淋巴器官的发育和维持方面存在严重缺陷。由于表面LT由淋巴细胞、自然杀伤细胞、淋巴组织起始细胞以及其他一些细胞类型表达，我们通过条件性基因靶向剖析了细胞类型特异性LT对复杂的LT缺陷表型的贡献。与完全缺乏LTβ的小鼠相比，B-LTβ基因敲除（KO）小鼠的脾脏表现出中间型表型。相反，T-LTβ KO小鼠的脾脏结构正常。然而，T细胞和B细胞中LTβ的失活导致脾脏边缘区结构和滤泡树突状细胞发育出现额外缺陷。B-LTβ KO小鼠以及T和B-LTβ KO小鼠的淋巴结（LN）和派尔集合淋巴结（PP）结构正常，只是PP的尺寸减小。在淋巴细胞特异性LT KO小鼠组中进行比较时，对T细胞依赖性抗原的抗体反应缺陷与脾脏结构缺陷的严重程度相关。B-LTβ KO小鼠以及T和B-LTβ KO小鼠的脾脏、LN和PP中CCL21和CCL19趋化因子的表达未受影响，而CXCL13仅在脾脏中略有降低。总体而言，我们的数据表明：（i）支持脾脏、LN和PP结构的LT信号需求不同；（ii）B细胞表达的LT复合物在维持脾脏结构中起主要作用，而T细胞表达的表面LT提供互补但不同的信号；（iii）在非转基因模型中，淋巴组织趋化因子的表达仅在最小程度上依赖于B和T淋巴细胞表面LT复合物的表达。
