CD154 Activates Macrophage Antimicrobial Activity in the Absence of IFN-γ through a TNF-α-Dependent Mechanism

Abstract

Protection against certain intracellular pathogens can take place in the absence of IFN-γ through mechanisms dependent on TNF-α. In this regard, patients with partial defect in IFN-γ receptor 1 are not susceptible to toxoplasmosis. Thus, we used a model of Toxoplasma gondii infection to investigate whether CD154 modulates IFN-γ-independent mechanisms of host protection. Human monocyte-derived macrophages treated with recombinant CD154 exhibited increased anti-T. gondii activity. The number of tachyzoites per 100 macrophages at 20 h postinfection was lower in CD154-treated macrophages compared with controls. This was accompanied by a decrease in the percentage of infected cells in CD154-treated macrophages at 20 h compared with 1 h postinfection. CD154-bearing cells also induced antimicrobial activity in T. gondii-infected macrophages. CD154 enhanced macrophage anti-T. gondii activity independently of IFN-γ. TNF-α mediated the effects of CD154 on macrophage anti-T. gondii activity. CD154 increased TNF-α production by T. gondii-infected macrophages, and neutralization of TNF-α inhibited the effect of CD154 on macrophage anti-T. gondii activity. These results demonstrate that CD154 triggers TNF-α-dependent antimicrobial activity in macrophages and suggest that CD154 regulates the mechanisms of host protection that take place when IFN-γ signaling is deficient.

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

“…Using neutralizing mAbs against IFN-␥ and macrophages from IFN-␥ Ϫ/Ϫ mice, we demonstrated that CD40-CD154 interaction, a pathway that mediates host protection against numerous intracellular pathogens (10 -16), activates IFN-␥-independent control of Toxoplasma gondii in human and mouse macrophages (17,18). These studies revealed that CD40 signaling worked through autocrine production of TNF-␣ (17).…”

“…These studies revealed that CD40 signaling worked through autocrine production of TNF-␣ (17). Interestingly, TNF-␣ alone cannot induce anti-T. gondii activity in macrophages (19 -21).…”

CD40, autophagy and Toxoplasma gondii

“…This effect is not only mediated by recombinant CD154 or an agonistic anti-CD40 mAb but also by CD154 expressed on the membrane of activated CD4 + T cells (Andrade et al 2005a). Killing of T. gondii tachyzoites induced by CD40 does not require IFN-γ, or effector molecules downstream of this cytokine: NOS2 and Immune Related GTPases (IRG) (Andrade et al 2003, 2005a. In addition, killing of the parasite is not mediated by the oxidative pathway or starvation for tryptophan (Andrade et al 2005a).…”

“…Importantly, studies in human and mouse macrophages demonstrated that pharmacological inhibition of lysosomal enzymes, vacuolar ATPase, PI3K (including the autophagy inhibitor 3-methyl adenine), knockdown of hVps34, expression of dominant negative Rab7, knockdown of Beclin 1 did not inhibit antimicrobial activity induced by IFN-γ but ablated CD40-induced toxoplasmacidal activity (Andrade et al 2006). The different mechanisms used by CD40 and IFN-γ to kill T. gondii may contribute to the cooperation observed between CD40 and IFN-γ to promote control of the parasite (Andrade et al 2003).…”

“…Therefore, CD154 + T. gondii-reactive activated CD4 + T cells likely trigger CD40 signaling in macrophages and resident microglia. CD40 stimulation of macrophages allows them to acquire toxoplasmacidal activity (Andrade et al 2003(Andrade et al , 2005a(Andrade et al , b, 2006. This effect is not only mediated by recombinant CD154 or an agonistic anti-CD40 mAb but also by CD154 expressed on the membrane of activated CD4 + T cells (Andrade et al 2005a).…”