The role of the Lymphotoxin beta receptor in innate immunity

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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.