The Journal of Experimental Medicine
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Published online 16 January 2001.
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© The Rockefeller University Press, 0022-1007/2001/1/239/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 2, January 15, 2001 239-246

Brief Definitive Report

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

Daniel R. Roacha, Helen Briscoeb, Bernardette Saundersa, Malcolm P. Francec, Sean Rimintona, and Warwick J. Brittona,b
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

Correspondence to: Warwick J. Britton, Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No. 6, Newtown NSW 2042, Australia. Tel:61-2-9515-5210 Fax:61-2-9351-3968 E-mail: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-{alpha} (LT{alpha}3) and lymphotoxin-ß (LTß) 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 LT{alpha}3 and membrane-bound LTß in the host response to aerosol Mycobacterium tuberculosis infection. To overcome the lack of peripheral lymph nodes in LT{alpha}-/- and LTß-/- mice, bone marrow chimeric mice were constructed. LT{alpha}-/- chimeras, which lack both secreted LT{alpha}3 and membrane-bound LTß (LT{alpha}1ß2 and LT{alpha}2ß1), were highly susceptible and succumbed 5 wk after infection. LTß-/- chimeras, which lack only the membrane-bound LTß, controlled the infection in a comparable manner to wild-type (WT) chimeric mice. T cell responses to mycobacterial antigens and macrophage responses in LT{alpha}-/- chimeras were equivalent to those of WT chimeras, but in LT{alpha}-/- chimeras, granuloma formation was abnormal. LT{alpha}-/- 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, LT{alpha}3 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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