TNF Receptor-Associated Factor 6-Dependent CD40 Signaling Primes Macrophages to Acquire Antimicrobial Activity in Response to TNF-α

Abstract

IFN-γ is considered an essential stimulus that allows macrophages to acquire activity against intracellular pathogens in response to a second signal such as TNF-α. However, protection against important pathogens can take place in the absence of IFN-γ through mechanisms that are still dependent on TNF-α. Engagement of CD40 modulates antimicrobial activity in macrophages. However, it is not known whether CD40 can replace IFN-γ as priming signal for induction of this response. We show that CD40 primes mouse macrophages to acquire antimicrobial activity in response to TNF-α. The effect of CD40 was not caused by modulation of IL-10 and TGF-β production or TNFR expression and did not require IFN-αβ signaling. Induction of antimicrobial activity required cooperation between TNFR-associated factor 6-dependent CD40 signaling and TNFR2. These results support a paradigm where TNFR-associated factor 6 signaling downstream of CD40 alters the pattern of response of macrophages to TNF-α leading to induction of antimicrobial activity.

CD40 Restrains In Vivo Growth ofToxoplasma gondiiIndependently of Gamma Interferon

“…We report that in vivo CD40 ligation increases TNF-␣ production by T. gondii-infected macrophages. The increase in production of this cytokine by macrophages is likely sufficient to trigger toxoplasmacidal activity in macrophages, since low concentrations of TNF-␣ fully synergize with CD40 to induce this effector response (2). Taken together, these findings suggest that CD40 is an important modulator of TNF-␣ signaling during T. gondii infection.…”

“…These findings are compatible with the evidence that TNF-␣ signaling takes center stage in host protection when IFN-␥-dependent mechanisms of resistance are deficient (40,41,45). In addition, this report provides an in vivo correlate to our in vitro studies where we report that CD40 synergizes with TNFR2 to induce macrophage anti-T. gondii activity (2).…”

CD40 Induces Anti-Toxoplasma gondii Activity in Nonhematopoietic Cells Dependent on Autophagy Proteins

“…mHEVc are CD40 Ϫ and thus were transfected with linearized pRSV.5 (neo-) plasmid encoding the extracellular domain of human CD40 with the intracellular domain of mouse CD40 (hmCD40) or with pRSV.5 alone (gifts from Gail Bishop, University of Iowa) (31). While primary human RPE can express CD40, ARPE-19 cells are CD40 Ϫ (32).…”

CD40, autophagy and Toxoplasma gondii

“…The TRAF6 binding site plays a dual role in the autophagic killing of T. gondii: it enhances autocrine production of TNF-α (Mukundan et al 2005) and TRAF6 signaling downstream of CD40 synergizes with TNF-α to activate autophagy (Subauste et al 2007a). As a result, autophagosomes are recruited around the parasitophorous vacuole and this is followed by Rab7-dependent fusion with late endosomes-lysosomes and killing of T. gondii (Andrade 2005b(Andrade , 2006 (Figure).…”