The CD40-autophagy pathway is needed for host protection despite IFN-γ-dependent immunity and CD40 induces autophagy via control of P21 levels

Jose Andres C Portillo, Genevieve Okenka, Erin Reed, Angela Subauste, Jennifer Van Grol, Katrin Gentil, Masaaki Komatsu, Keiji Tanaka, Gary Landreth, Beth Levine, Carlos S. Subauste

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

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. Autophagydeficient 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.

Original languageEnglish (US)
Article numbere14472
JournalPLoS One
Volume5
Issue number12
DOIs
StatePublished - 2010

Fingerprint

autophagy
Autophagy
Macrophages
Immunity
immunity
Toxoplasma gondii
neuroglia
Microglia
Machinery
Toxoplasma
Adaptive Immunity
Molecules
T-cells
macrophages
Pathogens
Up-Regulation
toxoplasmosis
mice
Proteins
Genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Portillo, J. A. C., Okenka, G., Reed, E., Subauste, A., Van Grol, J., Gentil, K., ... Subauste, C. S. (2010). The CD40-autophagy pathway is needed for host protection despite IFN-γ-dependent immunity and CD40 induces autophagy via control of P21 levels. PLoS One, 5(12), [e14472]. https://doi.org/10.1371/journal.pone.0014472

The CD40-autophagy pathway is needed for host protection despite IFN-γ-dependent immunity and CD40 induces autophagy via control of P21 levels. / Portillo, Jose Andres C; Okenka, Genevieve; Reed, Erin; Subauste, Angela; Van Grol, Jennifer; Gentil, Katrin; Komatsu, Masaaki; Tanaka, Keiji; Landreth, Gary; Levine, Beth; Subauste, Carlos S.

In: PLoS One, Vol. 5, No. 12, e14472, 2010.

Research output: Contribution to journalArticle

Portillo, JAC, Okenka, G, Reed, E, Subauste, A, Van Grol, J, Gentil, K, Komatsu, M, Tanaka, K, Landreth, G, Levine, B & Subauste, CS 2010, 'The CD40-autophagy pathway is needed for host protection despite IFN-γ-dependent immunity and CD40 induces autophagy via control of P21 levels', PLoS One, vol. 5, no. 12, e14472. https://doi.org/10.1371/journal.pone.0014472
Portillo, Jose Andres C ; Okenka, Genevieve ; Reed, Erin ; Subauste, Angela ; Van Grol, Jennifer ; Gentil, Katrin ; Komatsu, Masaaki ; Tanaka, Keiji ; Landreth, Gary ; Levine, Beth ; Subauste, Carlos S. / The CD40-autophagy pathway is needed for host protection despite IFN-γ-dependent immunity and CD40 induces autophagy via control of P21 levels. In: PLoS One. 2010 ; Vol. 5, No. 12.
@article{c49b58fbd10040b896236e36de29795b,
title = "The CD40-autophagy pathway is needed for host protection despite IFN-γ-dependent immunity and CD40 induces autophagy via control of P21 levels",
abstract = "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. Autophagydeficient 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.",
author = "Portillo, {Jose Andres C} and Genevieve Okenka and Erin Reed and Angela Subauste and {Van Grol}, Jennifer and Katrin Gentil and Masaaki Komatsu and Keiji Tanaka and Gary Landreth and Beth Levine and Subauste, {Carlos S.}",
year = "2010",
doi = "10.1371/journal.pone.0014472",
language = "English (US)",
volume = "5",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "12",

}

TY - JOUR

T1 - The CD40-autophagy pathway is needed for host protection despite IFN-γ-dependent immunity and CD40 induces autophagy via control of P21 levels

AU - Portillo, Jose Andres C

AU - Okenka, Genevieve

AU - Reed, Erin

AU - Subauste, Angela

AU - Van Grol, Jennifer

AU - Gentil, Katrin

AU - Komatsu, Masaaki

AU - Tanaka, Keiji

AU - Landreth, Gary

AU - Levine, Beth

AU - Subauste, Carlos S.

PY - 2010

Y1 - 2010

N2 - 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. Autophagydeficient 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.

AB - 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. Autophagydeficient 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.

UR - http://www.scopus.com/inward/record.url?scp=79251517741&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79251517741&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0014472

DO - 10.1371/journal.pone.0014472

M3 - Article

C2 - 21217818

AN - SCOPUS:79251517741

VL - 5

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 12

M1 - e14472

ER -