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Wednesday, July 22, 2015
Parasite manipulation of the invariant chain (Ii/CD74) and the peptide editor H2-DM affects MHC-II antigen presentation during Toxoplasma gondii infection
2015 Jul 20. pii: IAI.00415-15. [Epub ahead of print]
Toxoplasma gondii is an obligate intracellular protozoan parasite. This apicomplexan is the causative agent of toxoplasmosis, a leading cause of central nervous system disease in AIDS. It has long been known that T. gondii interferes with major histocompatibility complex (MHC)-II antigen presentation to attenuate CD4
T cell responses and establish persisting infections. Transcriptional down-regulation of MHC-II genes by T. gondii was previously established, but the precise mechanisms inhibiting MHC-II function are currently unknown. Here, we show that, in addition to transcriptional regulation of MHC-II, the parasite modulates the expression of key components of the MHC-II antigen presentation pathway, namely the MHC-II associated invariant chain (Ii or CD74) and the peptide editor H2-DM in professional antigen presenting cells (pAPCs). Genetic deletion of CD74 restored the ability of infected dendritic cells to present a parasite antigen in the context of MHC-II in vitro. CD74 mRNA and protein levels were surprisingly elevated in infected cells, whereas MHC-II and H2-DM expression was inhibited. CD74 accumulated mainly in the endoplasmic reticulum (ER), and this phenotype required live parasites, but not active replication. Finally, we compared the impact of genetic deletion of CD74 and H2-DM genes on parasite dissemination towards lymphoid organs in mice, as well as activation of CD4
T cells, and interferon gamma (IFNγ) levels during acute infection. Cyst burdens and survival during the chronic phase of infection were also evaluated in wild-type and knockout mice. These results highlight that the infection is influenced by multiple levels of parasite manipulation of the MHC-II antigen presentation pathway.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
[PubMed - as supplied by publisher]
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