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Autophagy degrades pathogens  in vitro . The autophagy gene  Atg5  has been reported to be required for IFN-γ-dependent host protection  in vivo . However, these protective effects occur independently of autophagosome formation. Thus, the  in vivo  role of classic autophagy in protection conferred by adaptive immunity and how adaptive immunity triggers autophagy are incompletely understood. Employing biochemical, genetic and morphological studies, we found that CD40 upregulates the autophagy molecule Beclin 1 in microglia and triggers killing of  Toxoplasma gondii  dependent on the autophagy machinery. Infected CD40 −/−  mice failed to upregulate Beclin 1 in microglia/macrophages  in vivo . Autophagy-deficient Beclin 1 +/−  mice, mice with deficiency of the autophagy protein Atg7 targeted to microglia/macrophages as well as CD40 −/−  mice exhibited impaired killing of  T. gondii  and were susceptible to cerebral and ocular toxoplasmosis. Susceptibility to toxoplasmosis occurred despite upregulation of IFN-γ, TNF-α and NOS2, preservation of IFN-γ-induced microglia/macrophage anti- T. gondii  activity and the generation of anti- T. gondii  T cell immunity. CD40 upregulated Beclin 1 and triggered killing of  T. gondii  by decreasing protein levels of p21, a molecule that degrades Beclin 1. These studies identified CD40-p21-Beclin 1 as a pathway by which adaptive immunity stimulates autophagy. In addition, they support that autophagy is a mechanism through which CD40-dependent immunity mediates  in vivo  protection and that the CD40-autophagic machinery is needed for host resistance despite IFN-γ.

The CD40-Autophagy Pathway Is Needed for Host Protection Despite IFN-Γ-Dependent Immunity and CD40 Induces Autophagy via Control of P21 Levels