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

Microbiology & Immunology

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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 (US)
Article number	4279
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06646-8
State	Published - Dec 1 2018

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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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), [4279]. https://doi.org/10.1038/s41467-018-06646-8

Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae. / Chandra, Shilpi; Gray, James; Kiosses, William B.; Khurana, Archana; Hitomi, Kaori; Crosby, Catherine M.; Chawla, Ashu; Fu, Zheng; Zhao, Meng; Veerapen, Natacha; Richardson, Stewart K.; Porcelli, Steven A.; Besra, Gurdyal; Howell, Amy R.; Sharma, Sonia; Peters, Bjoern; Kronenberg, Mitchell.

In: Nature communications, Vol. 9, No. 1, 4279, 01.12.2018.

Research output: Contribution to journal › Article › peer-review

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

Chandra, Shilpi ; Gray, James ; Kiosses, William B. ; Khurana, Archana ; Hitomi, Kaori ; Crosby, Catherine M. ; Chawla, Ashu ; Fu, Zheng ; Zhao, Meng ; Veerapen, Natacha ; Richardson, Stewart K. ; Porcelli, Steven A. ; Besra, Gurdyal ; Howell, Amy R. ; Sharma, Sonia ; Peters, Bjoern ; Kronenberg, Mitchell. / Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae. In: Nature communications. 2018 ; Vol. 9, No. 1.

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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",

note = "Funding Information: We want to thank Zbigniew Mikulski for his help with microscopy and Jason Greenbaum for help with bioinformatics analysis. We would also like to thank Hilde Cheroutre for reviewing the manuscript and Gisen Kim and Hitosh Iwaya for advice on T-cell stimulation and expansion. This project has been funded in part with NIH grants AI45053 (M.K.), AI71922 (M.K.), RC4 AI092763-01 (M.K.), U01 GM111849 (A.R.H.), AI45889 (S.A.P.), and equipment grant S10RR027366 to the La Jolla Institute flow cytometry core facility. K.H. is supported by Research fellowships of Japan Society for the Promotion of Science for young scientists{\textquoteright} and postdoctoral fellowship from the Uehara memorial foundation. C.M.C. is supported by American Lung Association Senior Research Training Fellowship RT-412662. M.Z. is supported by NIH training grant T32 AR064194.",

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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

N1 - Funding Information: We want to thank Zbigniew Mikulski for his help with microscopy and Jason Greenbaum for help with bioinformatics analysis. We would also like to thank Hilde Cheroutre for reviewing the manuscript and Gisen Kim and Hitosh Iwaya for advice on T-cell stimulation and expansion. This project has been funded in part with NIH grants AI45053 (M.K.), AI71922 (M.K.), RC4 AI092763-01 (M.K.), U01 GM111849 (A.R.H.), AI45889 (S.A.P.), and equipment grant S10RR027366 to the La Jolla Institute flow cytometry core facility. K.H. is supported by Research fellowships of Japan Society for the Promotion of Science for young scientists’ and postdoctoral fellowship from the Uehara memorial foundation. C.M.C. is supported by American Lung Association Senior Research Training Fellowship RT-412662. M.Z. is supported by NIH training grant T32 AR064194.

PY - 2018/12/1

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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.

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