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Brief Definitive Report

Secreted Lymphotoxin- Is Essential for the Control of an Intracellular Bacterial Infection

^a Centenary Institute of Cancer Medicine and Cell Biology, Newtown NSW 2042, Australia
^b Department of Medicine, University of Sydney, Sydney NSW 2006, Australia
^c Department of Veterinary Pathology, University of Sydney, Sydney NSW 2006, Australia
Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No. 6, Newtown NSW 2042, Australia.61-2-9351-396861-2-9515-5210

wbritton{at}medicine.usyd.edu.au

Although the essential role of tumor necrosis factor (TNF) in the control of intracellular bac-terial infection is well established, it is uncertain whether the related cytokines lymphotoxin- (LT₃) and lymphotoxin-β (LTβ) have independent roles in this process. Using C57Bl/6 mice in which the genes for these cytokines have been disrupted, we have examined the relative contribution of secreted LT₃ and membrane-bound LTβ in the host response to aerosol Mycobacterium tuberculosis infection. To overcome the lack of peripheral lymph nodes in LT^–/– and LTβ^–/– mice, bone marrow chimeric mice were constructed. LT^–/– chimeras, which lack both secreted LT₃ and membrane-bound LTβ (LT1β2 and LT2β1), were highly susceptible and succumbed 5 wk after infection. LTβ^–/– chimeras, which lack only the membrane-bound LTβ, controlled the infection in a comparable manner to wild-type (WT) chimeric mice. T cell responses to mycobacterial antigens and macrophage responses in LT^–/– chimeras were equivalent to those of WT chimeras, but in LT^–/– chimeras, granuloma formation was abnormal. LT^–/– chimeras recruited normal numbers of T cells into their lungs, but the lymphocytes were restricted to perivascular and peribronchial areas and were not colocated with macrophages in granulomas. Therefore, LT₃ is essential for the control of pulmonary tuberculosis, and its critical role lies not in the activation of T cells and macrophages per se but in the local organization of the granulomatous response.

Key Words: lymphotoxin • TNF • tuberculosis • granuloma • lung

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