The role of the Lymphotoxin beta receptor in innate immunity

光敏素b受体（LT β R）是肿瘤坏死因子受体（TNFR）核心家族的成员。LT β R控制个体发育过程中淋巴结和派伊尔淋巴结的形成。LT β R的已知配体是异源三聚体形式的细胞因子光毒素a /光毒素B（LTa 1 b 2）和同源三聚体形式的LIGHT（LIGHT 3）。我们小组最近的结果表明，LT β R缺陷小鼠不能控制细胞内细菌的感染，并在感染后5至10天内死亡。单核细胞增生李斯特菌的LD 50约为。与野生型对照（etwa 300.000 cfu）相比，LTbR-/-小鼠（etwa 3.000 cfu）中减少了2个对数级。然而，LTbb-/-小鼠在大肠杆菌感染后产生大量的TNF α和干扰素（IFNg），这表明在LT β R缺陷小鼠中，已建立的抗菌TNF/TNFRp 55或IFNg/IFNgR途径没有缺陷。这些数据表明LT β R在控制细胞内细菌中的一种迄今未知的主要功能。由于LT β R-/-动物缺乏淋巴结，因此可以假定这种缺陷导致天然免疫力受损。然而，LT β R-/-骨髓细胞的野生型受体在用细胞内细菌攻击后仍然高度易感，这表明LT β R在造血区室中的内在作用。有趣的是，LT β R和LT b缺陷小鼠在脾脏边缘区缺乏特异性巨噬细胞亚群（嗜金属巨噬细胞和边缘区巨噬细胞）。这些巨噬细胞亚群的假定功能之一是识别细菌和真菌细胞壁中经常发现的“外来”碳水化合物模式，随后激活先天免疫应答。我们已经可以证明，LT B-和LTa-缺陷小鼠在用Ti 1和Ti 2抗原攻击后具有受损的T细胞非依赖性B细胞应答。自然杀伤（NK）细胞的分化和效应功能似乎在这些动物中有缺陷。总之，我们的数据表明LT β R在对抗细胞内细菌的天然防御中起着迄今为止未知的作用。本研究的目的是鉴定分子抗菌效应系统和表征先天免疫系统的细胞群，这些细胞群在LT β R不存在的情况下是有缺陷的。

The lymphotoxin b-receptor (LTßR) is a member of the core family of tumor necrosis factor receptors (TNFR). The LTßR controls the formation of lymph nodes and Peyer´s patches during ontogeny. The known ligands for LTßR are the cytokines lymphotoxin a / lymphotoxin b in the form of a heterotrimer (LTa1b2) and LIGHT in the form of a homotrimer (LIGHT3). Recent results generated in our group indicate that LTßR-deficient mice are unable to control infections with intracellular bacteria and die within 5 to 10 days p.i.. The LD50 of Listeria monocytogenes organisms is approx. 2 log steps reduced in LTbR-/- mice (etwa 3.000 cfu) compared to wildtype controls (etwa 300.000 cfu). However, LTbb-/- mice produce high amounts of TNFa and interferong (IFNg) after listeria infection, demonstrating that the well-established antibacterial TNF/TNFRp55 or IFNg/IFNgR pathways are not defective in LTßR-deficient mice. These data suggest an hitherto unknown primary function of LTßR in the control of intracellular bacteria. Since LTßR-/- animals lack lymph nodes it might be assumed that this defect results in the impairment of natural immunity. However, wildtype recipients of LTßR-/- bone marrow cells are still highly susceptible after challenge with intracellular bacteria, suggesting an intrinsic role of the LTßR in the hematopoietic compartment. Interestingly, LTßR- and LTb-deficient mice lack specific macrophage subpopulations in the marginal zone of the spleen (metallophilic and marginal zone macophages). One of the postulated functions of these macrophage subpopulations is the recognition of "foreign" carbohydrate patterns regularly found in the cell walls of bacteria and fungi, with subsequent activation of innate immune responses. We could already show that LTb- and LTa-deficient mice have an impaired T cell independent B cell response after challenge with Ti1 and Ti2 antigens. Also the differentiation and effector function of natural killer (NK) cells appears to be defective in these animals. In summary, our data indicate that the LTßR plays an hitherto unknown role in the natural defence against intracellular bacteria. Aim of this study is the identification of the molecular antibacterial effector systems and the characterization of the cell populations of the innate immune system that are defective in the absence of the LTßR.