Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae

Shilpi Chandra, James Gray, William B. Kiosses, Archana Khurana, Kaori Hitomi, Catherine M. Crosby, Ashu Chawla, Zheng Fu, Meng Zhao, Natacha Veerapen, Stewart K. Richardson, Steven A. Porcelli, Gurdyal Besra, Amy R. Howell, Sonia Sharma, Bjoern Peters and Mitchell Kronenberg ()
Additional contact information
Shilpi Chandra: La Jolla Institute for Allergy and Immunology
James Gray: La Jolla Institute for Allergy and Immunology
William B. Kiosses: La Jolla Institute for Allergy and Immunology
Archana Khurana: La Jolla Institute for Allergy and Immunology
Kaori Hitomi: La Jolla Institute for Allergy and Immunology
Catherine M. Crosby: La Jolla Institute for Allergy and Immunology
Ashu Chawla: La Jolla Institute for Allergy and Immunology
Zheng Fu: La Jolla Institute for Allergy and Immunology
Meng Zhao: La Jolla Institute for Allergy and Immunology
Natacha Veerapen: University of Birmingham
Stewart K. Richardson: University of Connecticut
Steven A. Porcelli: Albert Einstein College of Medicine
Gurdyal Besra: University of Birmingham
Amy R. Howell: University of Connecticut
Sonia Sharma: La Jolla Institute for Allergy and Immunology
Bjoern Peters: La Jolla Institute for Allergy and Immunology
Mitchell Kronenberg: La Jolla Institute for Allergy and Immunology

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Invariant natural killer T cells (iNKT cells) are activated by lipid antigens presented by CD1d, but the pathway leading to lipid antigen presentation remains incompletely characterized. Here we show a whole-genome siRNA screen to elucidate the CD1d presentation pathway. A majority of gene knockdowns that diminish antigen presentation reduced formation of glycolipid-CD1d complexes on the cell surface, including members of the HOPS and ESCRT complexes, genes affecting cytoskeletal rearrangement, and ABC family transporters. We validated the role in vivo for the multidrug resistance protein 1 (Mrp1) in CD1d antigen presentation. Mrp1 deficiency reduces surface clustering of CD1d, which decreased iNKT cell activation. Infected Mrp1 knockout mice show decreased iNKT cell responses to antigens from Streptococcus pneumoniae and were associated with increased mortality. Our results highlight the unique cellular events involved in lipid antigen presentation and show how modification of this pathway can lead to lethal infection.

Date: 2018
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DOI: 10.1038/s41467-018-06646-8

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