Secreted lymphotoxin-alpha is essential for the control of an intracellular bacterial infection

Although the essential role of tumor necrosis factor (TNF) in the control o f intracellular bacterial infection is well established, it is uncertain wh ether the related cytokines lymphotoxin-alpha (LT alpha (3)) and lymphotoxi n-beta (LT beta) have independent roles in this process. Using C57B1/6 mice in which the genes for these cytokines have been disrupted, we have examin ed the relative contribution of secreted LT alpha (3) and membrane-bound LT P in the host response to aerosol Mycobacterium tuberculosis infection. To overcome the lack of peripheral lymph nodes in LT alpha (-/-) and LT beta ( -/-) mice, bone marrow chimeric mice were constructed. LT alpha (-/-) chime ras, which lack both secreted LT alpha (3) and membrane-bound LTP (LT alpha 1 beta2 and LT alpha2 beta1), were highly susceptible and succumbed 5 wk af ter infection. LT beta (-/-) chimeras, which lack only the membrane-bound L TP, controlled the infection in a comparable manner to wild-type (WT) chime ric mice. T cell responses to mycobacterial antigens and macrophage respons es 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 ly mphocytes were restricted to perivascular and peribronchial areas and were not colocated with macrophages in granulomas. Therefore, LT alpha (3), is e ssential for the control of pulmonary tuberculosis, and its critical role l ies not in the activation of T cells and macrophages per se but in the loca l organization of the granulomatous response.