The CD40/CD40 Ligand Interaction Is Required for Resistance to Toxoplasmic Encephalitis

Abstract

Since the CD40/CD40 ligand (CD40L) interaction is involved in the regulation of macrophage production of interleukin 12 (IL-12) and T-cell production of gamma interferon (IFN-␥), effector cell functions associated with resistance to Toxoplasma gondii, the role of CD40L in immunity to this parasite was assessed. Infection of C57BL/6 mice with T. gondii results in an upregulation of CD40 expression on accessory cell populations at local sites of infection as well as in lymphoid tissues. Splenocytes from C57BL/6 mice infected with T. gondii for 5 days produced high levels of IL-12 and IFN-␥ when stimulated with toxoplasma lysate antigen, and blocking CD40L did not significantly alter the production of IFN-␥ or IL-12 by these cells. Similar results were observed with splenocytes and mononuclear cells isolated from the brains of chronically infected mice. Interestingly, although CD40L؊/؊ mice infected with T. gondii produced less IL-12 than wild-type mice, they produced comparable levels of IFN-␥ but succumbed to toxoplasmic encephalitis 4 to 5 weeks after infection. The inability of CD40L؊/؊ mice to control parasite replication in the brain correlated with the ability of soluble CD40L, in combination with IFN-␥, to activate macrophages in vitro to control replication of T. gondii. Together, these results identify an important role for the CD40/CD40L interaction in resistance to T. gondii. However, this interaction may be more important in the control of parasite replication in the brain rather than the generation of protective T-cell responses during toxoplasmosis.The induction of a TH1-type immune response is critical for resistance to many intracellular pathogens, including Toxoplasma gondii (10). The events that lead to protective immunity are dependent on the production of interleukin 12 (IL-12), which drives the development of a TH1-type response dominated by the production of gamma interferon (IFN-␥). IFN-␥ is the major mediator of resistance to T. gondii (41) and is required for the activation of effector mechanisms that are essential for control of T. gondii (10). The importance of T cells in resistance to T. gondii is best illustrated by the patients with acquired immune deficiencies who develop toxoplasmic encephalitis (TE). For example, patients with certain cancers, or who are being actively immunosuppressed to allow successful transplantation, are susceptible to reactivation of toxoplasmosis (21, 36). Moreover, patients with AIDS become susceptible to TE as their T-cell counts fall (20), which correlates with a reduction in the levels of IFN-␥ that they can produce (11). The common characteristic of these patients is that they have an acquired defect in their T-cell functions that cripples the ability of the immune system to control T. gondii.Interestingly, a role for the CD40/CD40 ligand (CD40L) interaction in resistance to T. gondii is indicated by the development of TE in pediatric patients with a primary defect in this receptor-ligand interaction (24, 42). However, although the CD40/CD40L interactio...

IL‐33 receptor (T1/ST2) signalling is necessary to prevent the development of encephalitis in mice infected with Toxoplasma gondii

“…For example CD40-CD40L signalling appears to be sufficient for in vitro and in vivo killing of T. gondii independently of IFN-g or reactive nitrogen species [47,48]. Importantly, CD40/ CD40L signalling is critical for protection against TE with CD40L À/À mice demonstrating increased parasite proliferation [49].…”

“…For example CD40-CD40L signalling appears to be sufficient for in vitro and in vivo killing of T. gondii independently of IFN-g or reactive nitrogen species [47,48]. Importantly, CD40/ CD40L signalling is critical for protection against TE with CD40L À/À mice demonstrating increased parasite proliferation [49].In conclusion, during the course of our studies T1/ST2 was shown to be upregulated during T. gondii infection in the brain and demonstrated to have a protective role in resistant BALB/c mice as infected T1/ST2 À/À BALB/c mice showed increased susceptibility in comparison with infected WT mice. The increased susceptibility of T1/ST2 À/À mice was related to increased brain pathology that correlated with both increased parasite burden and greater cerebral expression of IFN-g, iNOS and TNF-a.…”

CD40, autophagy and Toxoplasma gondii

“…The role of macrophages/microglia as effector cells against T. gondii, the fact that mice deficient in the CD40 -CD154 pathway are susceptible to cerebral toxoplasmosis despite unimpaired upregulation of IFN-γ together with the demonstration that CD40 induces autophagic killing of T. gondii independently of IFN-γ/NOS2 strongly suggest a paradigm where two arms of immunity: one dependent on IFN-γ/NOS2 and another dependent of CD40-induced autophagy are required to control T. gondii in the brain. This paradigm can explain why IFN-γ is insufficient for control of T. gondii in neural tissue (Yap et al 1998, Reichmann et al 2000.…”

“…However, studies in mouse models of T. gondii infection indicate that this pathway also activates mechanisms of host resistance that act independently of IFN-γ (Reichmann 2000). CD154 -/-mice develop toxoplasmic encephalitis despite upregulation of IFN-γ in the brain that is similar to that of infected wild-type mice (Reichmann et al 2000).…”

“…How-ever, the role of this pathway is particularly important for control of the parasite in the brain. CD154 -/-mice are susceptible to toxoplasmic encephalitis (Reichmann 2000).…”