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

doi:10.1038/s41590-021-00903-7

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

Nat Immunol. 2021 Apr;22(4):497-509. doi: 10.1038/s41590-021-00903-7. Epub 2021 Mar 31.

Authors

Gaëtan Barbet^#^{1

2

3}, Priyanka Nair-Gupta^#^{4

5

6}, Michael Schotsaert^{7

8}, Stephen T Yeung^{9

10}, Julien Moretti^{1

2}, Fabian Seyffer¹¹, Giorgi Metreveli^{7

8}, Thomas Gardner^{12

13}, Angela Choi^{7

8

14}, Domenico Tortorella⁸, Robert Tampé¹⁵, Kamal M Khanna^{11

16}, Adolfo García-Sastre^{5

7

8

9}, J Magarian Blander^{17

18

19

20

21}

Affiliations

¹ The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA.
² Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
³ The Child Health Institute of New Jersey, and Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
⁴ Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Janssen Research and Development LLC, Spring House, PA, USA.
⁷ Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰ Division of Infectious Disease, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
¹¹ Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.
¹² Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, New York, NY, USA.
¹³ ArsenalBio, San Francisco, CA, USA.
¹⁴ Moderna Inc., Cambridge, MA, USA.
¹⁵ Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Frankfurt am Main, Germany.
¹⁶ Department of Microbiology, New York University School of Medicine, New York, NY, USA.
¹⁷ The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA. [email protected].
¹⁸ Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA. [email protected].
¹⁹ Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA. [email protected].
²⁰ Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. [email protected].
²¹ Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. [email protected].

^# Contributed equally.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Video-Audio Media

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 2 / genetics
ATP Binding Cassette Transporter, Subfamily B, Member 2 / metabolism*
ATP-Binding Cassette Transporters / genetics
ATP-Binding Cassette Transporters / metabolism*
Animals
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / virology
Cell Proliferation
Cells, Cultured
Coculture Techniques
Cross-Priming*
Dendritic Cells / immunology*
Dendritic Cells / metabolism
Dendritic Cells / virology
Disease Models, Animal
Endoplasmic Reticulum / immunology
Endoplasmic Reticulum / metabolism
Endoplasmic Reticulum / virology
Female
Golgi Apparatus / immunology
Golgi Apparatus / metabolism
Golgi Apparatus / virology
Histocompatibility Antigens Class I / immunology*
Histocompatibility Antigens Class I / metabolism
Host-Pathogen Interactions
Humans
Influenza A virus / immunology*
Influenza A virus / pathogenicity
Lymphocyte Activation
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Orthomyxoviridae Infections / genetics
Orthomyxoviridae Infections / immunology*
Orthomyxoviridae Infections / metabolism*
Orthomyxoviridae Infections / virology*

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 2
ATP-Binding Cassette Transporters
Histocompatibility Antigens Class I
Tap1 protein, mouse
transporter associated with antigen processing (TAP)

Abstract

Publication types

MeSH terms

Substances

Grants and funding