TAP dysfunction in dendritic cells enables noncanonical cross-presentation for T cell priming

Gaëtan Barbet, Priyanka Nair-Gupta, Michael Schotsaert, Stephen T. Yeung, Julien Moretti, Fabian Seyffer, Giorgi Metreveli, Thomas Gardner, Angela Choi, Domenico Tortorella, Robert Tampé, Kamal M. Khanna, Adolfo García-Sastre, J. Magarian Blander

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)497-509
Number of pages13
JournalNature Immunology
Issue number4
StatePublished - Apr 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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