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; Mitchell Kronenberg

doi:10.1038/s41467-018-06646-8

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, Mitchell Kronenberg

Biosciences

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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.

Original language	English
Article number	4279
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06646-8
Publication status	Published - 15 Oct 2018

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Chandra_et_al_Mrp1_is_involved_in_lipid_Nature_Communications_2018
Checked for eligibility 22/10/2018 First published in Nature Communications https://doi.org/10.1038/s41467-018-06646-8
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Chandra, S., Gray, J., Kiosses, W. B., Khurana, A., Hitomi, K., Crosby, C. M., Chawla, A., Fu, Z., Zhao, M., Veerapen, N., Richardson, S. K., Porcelli, S. A., Besra, G., Howell, A. R., Sharma, S., Peters, B., & Kronenberg, M. (2018). Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae. Nature Communications, 9(1), Article 4279. https://doi.org/10.1038/s41467-018-06646-8

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title = "Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae",

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.",

author = "Shilpi Chandra and James Gray and Kiosses, {William B} and Archana Khurana and Kaori Hitomi and Crosby, {Catherine M} and Ashu Chawla and Zheng Fu and Meng Zhao and Natacha Veerapen and Richardson, {Stewart K} and Porcelli, {Steven A} and Gurdyal Besra and Howell, {Amy R} and Sonia Sharma and Bjoern Peters and Mitchell Kronenberg",

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Chandra, S, Gray, J, Kiosses, WB, Khurana, A, Hitomi, K, Crosby, CM, Chawla, A, Fu, Z, Zhao, M, Veerapen, N, Richardson, SK, Porcelli, SA, Besra, G, Howell, AR, Sharma, S, Peters, B & Kronenberg, M 2018, 'Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae', Nature Communications, vol. 9, no. 1, 4279. https://doi.org/10.1038/s41467-018-06646-8

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T1 - Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae

AU - Chandra, Shilpi

AU - Gray, James

AU - Kiosses, William B

AU - Khurana, Archana

AU - Hitomi, Kaori

AU - Crosby, Catherine M

AU - Chawla, Ashu

AU - Fu, Zheng

AU - Zhao, Meng

AU - Veerapen, Natacha

AU - Richardson, Stewart K

AU - Porcelli, Steven A

AU - Besra, Gurdyal

AU - Howell, Amy R

AU - Sharma, Sonia

AU - Peters, Bjoern

AU - Kronenberg, Mitchell

PY - 2018/10/15

Y1 - 2018/10/15

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-018-06646-8

DO - 10.1038/s41467-018-06646-8

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C2 - 30323255

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4279

ER -

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

Abstract

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