CD40 Restrains In Vivo Growth ofToxoplasma gondiiIndependently of Gamma Interferon

Abstract

CD40-CD154 interaction is pivotal for resistance against numerous pathogens. However, it is not known if this pathway can also enhance in vivo resistance in gamma interferon (IFN-␥)-deficient hosts. This is an important question because patients and mice with defects in type 1 cytokine response can control a variety of pathogens. While blockade of endogenous CD154 resulted in a remarkable increase in parasite load in IFN-␥ ؊/؊ mice infected with Toxoplasma gondii, in vivo administration of a stimulatory anti-CD40 monoclonal antibody markedly reduced parasite load. This latter effect took place even in T-cell-depleted mice and was accompanied by induction of macrophage toxoplasmacidal activity. CD40 stimulation restricted T. gondii replication independently of STAT1, p47 GTPases, and nitric oxide. In vivo CD40 ligation enhanced tumor necrosis factor alpha (TNF-␣) production by T. gondii-infected macrophages. In addition, CD40 stimulation required the presence of TNF receptor 2 to reduce parasite load in vivo. These results suggest that CD40-CD154 interaction regulates IFN-␥-independent mechanisms of host protection through induction of macrophage antimicrobial activity and modulation of TNF-␣ signaling.

CD40 Mediates Retinal Inflammation and Neurovascular Degeneration

“…After treatment with DNase (Ambion), 0.5 g of RNA was used to generate cDNA using oligo(dT) [12][13][14][15][16][17][18] primers and Superscript III reverse transcriptase (Invitrogen Life Technologies) as we described (29). cDNA (2.5 l) was used as template for RT-PCR using SYBR Green PCR Master Mix (Applied Biosystems) and 20 pM (each) primers in a final volume of 50 l. Primer sequences for NOS2 (30), COX-2 (31), ICAM-1 (30), keratinocyte-derived chemokine (KC)/CXCL1 (32), MCP-1 (33), and 18S rRNA (29) were previously described.…”

“…CD40 is a member of the TNFR superfamily that regulates many aspects of cellular and humoral immunity (11)(12)(13). CD40 is a regulator of inflammatory disorders, and studies using nonocular cells revealed that the CD40 induces NOS2 and COX-2, triggers chemokine production (MCP-1, IL-8, and MIP-2), and up-regulates ICAM-1 (14 -19).…”

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

“…Furthermore Scheidegger et al (2005) showed that TNF-a treatment resulted in increased parasite proliferation in cultures of infected rat brain slices although the mechanisms remain obscure [46]. Recent reports have highlighted the existence of IFN-g independent means of T. gondii killing [47,48]. 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].…”

“…Recent reports have highlighted the existence of IFN-g independent means of T. gondii killing [47,48]. 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].…”

“…Of significance these workers had previously demonstrated that IFN-g and TNF-a were insufficient to control the growth of T. gondii in neurones [45]. Furthermore Scheidegger et al (2005) showed that TNF-a treatment resulted in increased parasite proliferation in cultures of infected rat brain slices although the [47,48]. 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].…”