Role of lymphotoxin in lymphoid organogenesis and contact hypersensitivity.

我们已经证实，在脾脏中，光敏素和TNF受体-I（TNFR-I）在生发中心（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，我们已经调查的作用，在建立脾脏FDC和GC结构，利用相互骨髓移植的光毒素和TNFR-I。当用补体受体1和2（CR 1/2）缺陷的骨髓细胞重建光敏素缺陷小鼠时，用抗CR 1/2单克隆抗体鉴定了有组织的FDC网络，表明FDC来自光敏素缺陷的受体。因此，从非骨髓前体细胞成熟FDC需要在骨髓来源的细胞中而不是在非骨髓来源的细胞中表达α-光敏素。通过骨髓移植，我们还能够证明，脾脏中FDC网络和GC的形成是由表达光敏素的骨髓来源细胞和表达TNFR-I的非骨髓来源细胞控制的。由于光敏素主要由Th 1型辅助性T细胞产生，我们还测试了光敏素在体内诱导接触性超敏反应中的作用，接触性超敏反应是迟发型超敏反应的原型，用的是缺乏光敏素的小鼠。我们已经发现，在用苯基三甲基氨基苯胺（TMA）抗原攻击后，光敏素缺陷小鼠表现出显著受损的足垫肿胀。利用相互骨髓移植，我们已经证明，在接触性超敏反应受损的光敏素缺陷小鼠是由于受损的皮肤中的骨髓来源的细胞的功能，这是必不可少的接触性超敏反应的致敏阶段。这些研究清楚地表明，光敏素起着至关重要的作用，不仅在淋巴器官的形成，而且在接触性超敏反应。

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.