The ability to activate macrophages in vitro for nitric oxide production and killing of Leishmania major parasites is dependent on tumor necrosis factor, although L. major-infected mice lacking the TNF receptor p55 (TNFRp55 ؊/؊ mice) or both the TNFRp55 and TNFRp75 (TNFRp55p75 ؊/؊ mice) are able to produce NO in vivo and eliminate the parasites. Here we report that activated T cells cocultured with macrophages results in TNFR-independent activation sufficient to control parasites and that both CD40/CD40L and LFA-1 contribute to T-cell-mediated macrophage activation. Thus, anti-CD3-stimulated T cells activated TNFR-deficient macrophages, while T cells from CD40L ؊/؊ mice were partially defective in triggering NO production by TNFRp55p75 ؊/؊ macrophages. Moreover, in the presence of gamma interferon, anti-CD40 monoclonal antibody (MAb) activated TNFR-deficient macrophages. Finally, MAb blockade of LFA-1 completely inhibited macrophage NO production. Our data indicate that T cells can activate macrophages in the absence of TNF, thus providing a mechanism for how TNFR-deficient mice can control intracellular pathogens.The protozoan parasite Leishmania major infects mononuclear phagocytes, and control of infection depends on adequate activation of the infected macrophages to kill parasites and inhibit their replication (15). In vitro studies with murine macrophages revealed that soluble factors secreted by activated T cells mediate activation of macrophages to produce nitric oxide (NO), resulting in killing or control of L. major parasites (2). Macrophage activation by soluble factors (cytokines) depends on gamma interferon (IFN-␥) as well as tumor necrosis factor (TNF) (11,12,19,41). Optimal NO production occurs in macrophages via upregulation of inducible nitric oxide synthase (iNOS) mRNA, which is itself optimally induced when IFN regulatory factor 1 is upregulated by IFN-␥, and NF-B is activated by a second signal (22,32). TNF has been shown to be a major NF-B-activating signal for macrophage activation. Thus, IFN-␥ and autocrine secretion of TNF by macrophages are sufficient to mediate production of NO and killing of L. major parasites (11,18).We previously demonstrated that macrophages derived from TNFR (TNF receptor)p55 Ϫ/Ϫ or TNFRp55p75 Ϫ/Ϫ mice failed to produce NO and control parasites upon stimulation with IFN-␥ in vitro, whereas TNFRp75 Ϫ/Ϫ mice lacked this defect (25). This suggested that the TNF dependence of in vitro macrophage activation to produce NO and kill parasites was mediated by the TNFRp55. However, work with receptor knockouts, soluble TNFR-Ig (immunoglobulin) overexpression transgenics, and neutralizing antibodies show that TNF is not required for in vivo control of parasites, for the development of the type 1 IFN-␥ response to antigen restimulation, or for upregulation of iNOS at the site of infection in vivo (9,20,25,42,44). These data suggest that an in vivo mechanism exists that permits macrophages to produce NO and control parasites independent of TNF.Since T cells are present in the le...
TNF is involved in host resistance to several pathogens. Recently it was found that mice lacking the p55 receptor for TNF (TNFRp55 -/-) do not control growth of the intracellular bacteria, Listeria monocytogenes and Mycobacterium tuberculosis. Here we report that the course of infection in TNFRp55 -/- mice with another intracellular pathogen, the protozoan parasite Leishmania major, is also quite different from normal mice. TNFRp55 -/- mice developed larger lesions than control mice and failed to resolve these lesions. However, they were able to eliminate parasites within the lesions. Histologic analysis indicated that at late stages lesions from TNFRp55 -/- mice appeared similar to lesions associated with cutaneous graft-vs-host disease. Both TNFRp55 -/- and control mice developed a normal Th1-type response during infection. We also found that IFN-gamma-activated macrophages from TNFRp55 -/- mice produced nitric oxide and killed L. major in vitro, which correlated with the ability of TNFRp55 -/- mice to eliminate the parasites in vivo. The production of nitric oxide by macrophages from TNFRp55 -/- mice required the presence of the parasites, however, since in their absence TNF could only synergize with IFN-gamma for nitric oxide production when added to normal, but not TNFRp55 -/-, macrophages. These results indicate that neither macrophage microbicidal activity nor nitric oxide production is absolutely dependent on the p55 receptor for TNF. Furthermore, they uncover a previously undefined role for TNFRp55 in resolution of parasite-induced inflammatory lesions.
TNF participates in the induction of nitric oxide (NO) production and macrophage activation, leading to the elimination of intracellular pathogens. We previously found that TNF receptor p55-deficient mice (TNFRp55−/−) control replication of Leishmania major in vivo but fail to resolve their lesions. Here we report that mice lacking the p75 receptor (TNFRp75−/−) or both receptors (TNFRp55p75−/−), also control parasite replication, albeit mice lacking the p55 receptor (either TNFRp55−/− or TNFRp55p75−/−) are delayed in their elimination of L. major compared with controls. All TNF receptor-deficient mice developed a Th1-type immune response and up-regulated inducible NO synthase (iNOS) mRNA gene expression in lesions during infection. Thus, neither TNF receptor appears to be absolutely required for NO production or elimination of L. major in vivo. In vitro, however, while macrophages from naive TNFRp75−/− mice could be activated to produce NO and kill L. major, we observed a defect in NO production and parasite killing by resident peritoneal macrophages from naive TNFRp55−/− or TNFRp55p75−/− mice. However, when macrophages were elicited with leishmanial Ag from 4-wk-infected TNFRp55−/−or TNFRp55p75−/− mice, they produced NO and were leishmanicidal. These data suggest that the TNFRp75 plays no essential role in L. major infection in mice and that the p55 receptor may be required for optimal macrophage activation. However, the results also show that a mechanism exists by which macrophages can be primed in vivo during L. major infection to produce NO and kill L. major in the absence of signaling through either of the TNF receptors.
The elimination of lymphocytes within inflammatory lesions is a critical component in the resolution of disease once pathogens have been cleared. We report here that signaling through the TNF receptor p55 (TNFRp55) is required to eliminate lymphocytes from lesions associated with intracellular pathogens. Thus, TNFRp55−/− mice, but not Fas-deficient mice, maintained inflammatory lesions associated with either Leishmania major or Rhodococcus equi infection, although they developed a Th1 response and controlled the pathogens. Inflammatory cells from either L. major- or R. equi-infected C57BL/6 mice were sensitive to TNF-induced apoptosis, and conversely the number of apoptotic cells in the lesions from TNFRp55−/− mice was dramatically reduced compared with wild-type mice. Furthermore, in vivo depletion of TNF in wild-type mice blocked lesion regression following R. equi infection. Taken together, our results suggest that signaling through the TNFRp55, but not Fas, is required to induce apoptosis of T cells within inflammatory lesions once pathogens are eliminated, and that in its absence lesions fail to regress.
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