Journal
NATURE IMMUNOLOGY
Volume 22, Issue 4, Pages 497-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41590-021-00903-7
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Funding
- NIH [F32CA224438, 5R24 CA095823-04, S10 RR0 9145-01, AI073899, AI123284, DK111862, AI127658]
- NSF [DBI-9724504]
- NIH/NIAID Center for Research on Influenza Pathogenesis contract, CEIRS Network [HHSN266200700010C, AI101820, AI112318, AI143861]
- German Research Foundation [SFB 807, TA157/7]
- European Research Council (ERC) [789121]
- Burroughs Wellcome Fund
- Leukemia and Lymphoma Society
- Crohn's and Colitis Foundation
- American Heart Association pre-doctoral fellowship
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The study explains how viruses target host cell antigen-processing pathways, focusing on MHC-I molecules and the re-routing of ERGIC-resident MHC molecules to phagosomal vesicles for cross-presentation. It suggests that even without TAP, protective CD8(+) T cells can still be mobilized during viral infection, highlighting a noncanonical cross-presentation pathway.
Viral pathogens frequently target host cell antigen-processing pathways, including MHC-I-TAP peptide transporters, to evade host immunity. Blander and colleagues describe how MHC-I molecules can still cross-present antigen by re-routing ERGIC-resident MHC molecules to phagosomal vesicles, where phagolysosomal proteases act to shape the peptide repertoire for MHC-I presentation. Classic major histocompatibility complex class I (MHC-I) presentation relies on shuttling cytosolic peptides into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). Viruses disable TAP to block MHC-I presentation and evade cytotoxic CD8(+) T cells. Priming CD8(+) T cells against these viruses is thought to rely solely on cross-presentation by uninfected TAP-functional dendritic cells. We found that protective CD8(+) T cells could be mobilized during viral infection even when TAP was absent in all hematopoietic cells. TAP blockade depleted the endosomal recycling compartment of MHC-I molecules and, as such, impaired Toll-like receptor-regulated cross-presentation. Instead, MHC-I molecules accumulated in the ER-Golgi intermediate compartment (ERGIC), sequestered away from Toll-like receptor control, and coopted ER-SNARE Sec22b-mediated vesicular traffic to intersect with internalized antigen and rescue cross-presentation. Thus, when classic MHC-I presentation and endosomal recycling compartment-dependent cross-presentation are impaired in dendritic cells, cell-autonomous noncanonical cross-presentation relying on ERGIC-derived MHC-I counters TAP dysfunction to nevertheless mediate CD8(+) T cell priming.
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