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

Abstract

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-α (LTα3) 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 LTα3 and membrane-bound LTβ in the host response to aerosol Mycobacterium tuberculosis infection. To overcome the lack of peripheral lymph nodes in LTα−/− and LTβ−/− mice, bone marrow chimeric mice were constructed. LTα−/− chimeras, which lack both secreted LTα3 and membrane-bound LTβ (LTα1β2 and LTα2β1), 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 LTα−/− chimeras were equivalent to those of WT chimeras, but in LTα−/− chimeras, granuloma formation was abnormal. LTα−/− 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, LTα3 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.

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

“…4C). TNF-b, which has been shown to promote the local organization of the granulomatous response within the M. tuberculosis-infected tissue [13], was down-regulated in lungs of both IL-18-and MyD88-deficient mice, too (Fig. 4C).…”

“…This suggests that these T cells were functionally inhibited in the infected tissue probably due to the local cytokine environment in these mice. Both IL-18 and MyD88 KO lungs show diminished expression of TNF-b, which is directly involved in organization of granulomas in mycobacterial infection [13]. Furthermore, up-regulation of arginase-1 could result in a negative nitrogen balance within the lung tissue by depletion of arginine, which is an important micronutrient for T-cell proliferation and cytokine synthesis [29,35].…”

The Lymphotoxin β Receptor Is Critically Involved in Controlling Infections with the Intracellular Pathogens Mycobacterium tuberculosis and Listeria monocytogenes

“…In combination with the membranebound LT␤, LT␣ binds as the LT␣ 1 ␤ 2 heterotrimer to the LT␤R (16,21,23,24). TNF 3 , LT␣ 3 in concert with the TNFRp55, were shown to be of critical importance for the host defense against intracellularly replicating bacterial pathogens and for the formation and maintenance of fully differentiated granulomas (25)(26)(27)(28)(29)(30)(31). In contrast, the detailed role of the LT␤R and its cognate ligands in antimicrobial resistance and granuloma formation has remained unexplored.…”

Tuning inflammation in tuberculosis: the role of decoy receptors

“…Failure to resolve ongoing inflammation is an invariable key feature of pathologies, which are typically characterized by the high-level expression of inflammatory cytokines and chemokines [34]. TNFa and the related cytokine lymphotoxin [35] are potent pro-inflammatory cytokines with a wide range of activities in both the inflammatory and immune responses, and they play an essential role in host resistance against infection with M. tuberculosis and other mycobacteria [36]. TNFa-deficient mice infected by aerosol with M. tuberculosis develop normal T cell responses to mycobacterial antigens, but because of the failure of granuloma formation in the infected organs they are profoundly susceptible to the infection, succumbing with extensive necrosis in the lungs and infected organs [36].…”