Role of lymphotoxin in lymphoid organogenesis and contact hypersensitivity.

我们已经证明淋巴毒素和肿瘤坏死因子受体-I(TNFR-I)在脾中生发中心(GC)和滤泡树突状细胞(FDC)网络的形成中起重要作用。在本研究中，我们研究了淋巴毒素和TNFR-I在利用双向骨髓移植建立脾FDC和GC结构中的作用。用补体受体1和补体受体2(CR1/2)缺陷的骨髓细胞重组淋巴毒素缺陷小鼠，用抗CR1/2的单抗鉴定有组织的FDC网络，表明FDC来源于淋巴毒素缺陷受体。因此，淋巴毒素在骨髓来源的细胞中的表达，而不是在非骨髓来源的细胞中的表达，是非骨髓前体细胞分化成熟所必需的。通过骨髓移植，我们还证明了脾内FDC网络和GC的形成既受表达淋巴毒素的骨髓来源细胞控制，也受表达TNFR-I的非骨髓来源细胞控制。由于淋巴毒素主要由Th1型辅助性T细胞产生，我们还在体内测试了淋巴毒素在淋巴毒素缺陷小鼠诱发接触性超敏反应中的作用。我们发现淋巴毒素缺乏的小鼠在用苯三甲氨基苯胺(TMA)抗原攻击后表现出显著的足垫肿胀。通过双向骨髓移植，我们证明淋巴毒素缺陷小鼠的接触性超敏反应受损是由于皮肤中骨髓源细胞的功能受损，而皮肤细胞是接触性超敏反应的致敏阶段所必需的。这些研究清楚地表明，淋巴毒素不仅在淋巴器官的发生中起重要作用，而且在接触性超敏反应中也起着重要作用。

We have already demonstrated that both lymphotoxin and TNF receptor-I(TNFR-I) play essential roles in the formation of germinal centers (GC) and follicular dendritic cell (FDC) network in the spleen. In the present study, we have investigated the role, of lymphotoxin and TNFR-I in the establishment of spleen FDC and GC structure using reciprocal bone marrow transfer. When lymphotoxin-deficient mice were reconstituted with complement receptor 1 and 2(CR1/2)-deficient bone marrow cells, organized FDC network was identified with anti-CR1/2 monoclonal antibodies, indicating that FDC were derived from lymphotoxin-deficient recipient. Thus, expression of lymphotoxin in the bone marrow-derived cells, but not in the non-bone marrow-derived cells, is required for the maturation of FDC from non-bone marrow precursor cells. Using bone marrow transfer, we were also able to show that formation of FDC network and GC in the spleen are controlled by both lymphotoxin-expressing bone marrow-derived cells and by TNFR-I-expressing non-bone marrow-derived cells.Because lymphotoxin is mainly produced by Th1 type helper T cells, we have also tested in vivo role of lymphotoxin in the induction of contact hypersensitivity, a prototype of delayed-type hypersensitivity reaction, with lymphotoxin-deficient mice. We have found that lymphotoxin-deficient mice exhibit dramatic impaired footpad swelling after antigenic challenge with phenyltrimethylaminoaniline (TMA). Using reciprocal bone marrow transfer, we have demonstrated that impaired contact hypersensitivity in lymphotoxin-deficient mice is due to the impaired function of bone marrow-derived cells in the skin which is essential for the sensitization phase of contact hypersensitivity reaction.These studies clearly demonstrate that lymphotoxin plays an essential role not only in the lymphoid organogenesis but also in the contact hypersensitivity.