A reductionist cell-free major histocompatibility complex class II antigen processing system identifies immunodominant epitopes

Isamu Z. Hartman; Aeryon Kim; Robert J. Cotter; Kimberly Walter; Sarat K. Dalai; Tatiana Boronina; Wendell Griffith; David E. Lanar; Robert Schwenk; Urszula Krzych; Robert N. Cole; Scheherazade Sadegh-Nasseri

doi:10.1038/nm.2248

A reductionist cell-free major histocompatibility complex class II antigen processing system identifies immunodominant epitopes

Isamu Z. Hartman, Aeryon Kim, Robert J. Cotter, Kimberly Walter, Sarat K. Dalai, Tatiana Boronina, Wendell Griffith, David E. Lanar, Robert Schwenk, Urszula Krzych, Robert N. Cole, Scheherazade Sadegh-Nasseri

School of Medicine

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

45 Scopus citations

Abstract

Immunodominance is defined as restricted responsiveness of T cells to a few selected epitopes from complex antigens. Strategies currently used for elucidating CD4⁺ T cell epitopes are inadequate. To understand the mechanism of epitope selection for helper T cells, we established a cell-free antigen processing system composed of defined proteins: human leukocyte antigen-DR1 (HLA-DR1), HLA-DM and cathepsins. Our reductionist system successfully identified the physiologically selected immunodominant epitopes of two model antigens: hemagglutinin-1 (HA1) from influenza virus (A/Texas/1/77) and type II collagen (CII). When applied for identification of new epitopes from a recombinant liver-stage antigen of malaria falciparum (LSA-NRC) or HA1 from H5N1 influenza virus ('avian flu'), the system selected single epitopes from each protein that were confirmed to be immunodominant by their capacity to activate CD4⁺ T cells from H5N1-immunized HLA-DR1-transgenic mice and LSA-NRC-vaccinated HLA-DR1-positive human volunteers. Thus, we provide a new tool for the identification of physiologically relevant helper T cell epitopes from antigens.

Original language	English (US)
Pages (from-to)	1333-1340
Number of pages	8
Journal	Nature medicine
Volume	16
Issue number	11
DOIs	https://doi.org/10.1038/nm.2248
State	Published - Nov 2010

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Hartman, I. Z., Kim, A., Cotter, R. J., Walter, K., Dalai, S. K., Boronina, T., Griffith, W., Lanar, D. E., Schwenk, R., Krzych, U., Cole, R. N., & Sadegh-Nasseri, S. (2010). A reductionist cell-free major histocompatibility complex class II antigen processing system identifies immunodominant epitopes. Nature medicine, 16(11), 1333-1340. https://doi.org/10.1038/nm.2248

@article{cd883fcf54a34b62b4d31bb47934e056,

title = "A reductionist cell-free major histocompatibility complex class II antigen processing system identifies immunodominant epitopes",

abstract = "Immunodominance is defined as restricted responsiveness of T cells to a few selected epitopes from complex antigens. Strategies currently used for elucidating CD4+ T cell epitopes are inadequate. To understand the mechanism of epitope selection for helper T cells, we established a cell-free antigen processing system composed of defined proteins: human leukocyte antigen-DR1 (HLA-DR1), HLA-DM and cathepsins. Our reductionist system successfully identified the physiologically selected immunodominant epitopes of two model antigens: hemagglutinin-1 (HA1) from influenza virus (A/Texas/1/77) and type II collagen (CII). When applied for identification of new epitopes from a recombinant liver-stage antigen of malaria falciparum (LSA-NRC) or HA1 from H5N1 influenza virus ('avian flu'), the system selected single epitopes from each protein that were confirmed to be immunodominant by their capacity to activate CD4+ T cells from H5N1-immunized HLA-DR1-transgenic mice and LSA-NRC-vaccinated HLA-DR1-positive human volunteers. Thus, we provide a new tool for the identification of physiologically relevant helper T cell epitopes from antigens.",

author = "Hartman, {Isamu Z.} and Aeryon Kim and Cotter, {Robert J.} and Kimberly Walter and Dalai, {Sarat K.} and Tatiana Boronina and Wendell Griffith and Lanar, {David E.} and Robert Schwenk and Urszula Krzych and Cole, {Robert N.} and Scheherazade Sadegh-Nasseri",

note = "Funding Information: We wish to thank S. Landry, A. Hamad, J. Pomerantz and K. Narayan for reading the manuscript and insightful discussions, S. Khoruzhenko for protein production, S. Kalb-Ramirez and D. Wang for the initial mass spectrometry, F. Korangy and D. Pardoll (Johns Hopkins University) for Escherichia coli transformed with an expression vector encoding influenza HA, D. Zaller (Merck) for the original DR1-transgenic mice, L. Rein for testing the human samples and the US National Institutes of Health Tetramer Facility for providing DR1 and CLIP monomers. This work was supported by R01 grants AI063764 and GM053549, a grant from Johns Hopkins Malaria Research Institute to S.S.-N., a US National Science Foundation predoctoral award to I.Z.H. and a Johns Hopkins University Rheumatology T32 Fellowship to A.K.",

year = "2010",

month = nov,

doi = "10.1038/nm.2248",

language = "English (US)",

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T1 - A reductionist cell-free major histocompatibility complex class II antigen processing system identifies immunodominant epitopes

AU - Hartman, Isamu Z.

AU - Kim, Aeryon

AU - Cotter, Robert J.

AU - Walter, Kimberly

AU - Dalai, Sarat K.

AU - Boronina, Tatiana

AU - Griffith, Wendell

AU - Lanar, David E.

AU - Schwenk, Robert

AU - Krzych, Urszula

AU - Cole, Robert N.

AU - Sadegh-Nasseri, Scheherazade

N1 - Funding Information: We wish to thank S. Landry, A. Hamad, J. Pomerantz and K. Narayan for reading the manuscript and insightful discussions, S. Khoruzhenko for protein production, S. Kalb-Ramirez and D. Wang for the initial mass spectrometry, F. Korangy and D. Pardoll (Johns Hopkins University) for Escherichia coli transformed with an expression vector encoding influenza HA, D. Zaller (Merck) for the original DR1-transgenic mice, L. Rein for testing the human samples and the US National Institutes of Health Tetramer Facility for providing DR1 and CLIP monomers. This work was supported by R01 grants AI063764 and GM053549, a grant from Johns Hopkins Malaria Research Institute to S.S.-N., a US National Science Foundation predoctoral award to I.Z.H. and a Johns Hopkins University Rheumatology T32 Fellowship to A.K.

PY - 2010/11

Y1 - 2010/11

N2 - Immunodominance is defined as restricted responsiveness of T cells to a few selected epitopes from complex antigens. Strategies currently used for elucidating CD4+ T cell epitopes are inadequate. To understand the mechanism of epitope selection for helper T cells, we established a cell-free antigen processing system composed of defined proteins: human leukocyte antigen-DR1 (HLA-DR1), HLA-DM and cathepsins. Our reductionist system successfully identified the physiologically selected immunodominant epitopes of two model antigens: hemagglutinin-1 (HA1) from influenza virus (A/Texas/1/77) and type II collagen (CII). When applied for identification of new epitopes from a recombinant liver-stage antigen of malaria falciparum (LSA-NRC) or HA1 from H5N1 influenza virus ('avian flu'), the system selected single epitopes from each protein that were confirmed to be immunodominant by their capacity to activate CD4+ T cells from H5N1-immunized HLA-DR1-transgenic mice and LSA-NRC-vaccinated HLA-DR1-positive human volunteers. Thus, we provide a new tool for the identification of physiologically relevant helper T cell epitopes from antigens.

AB - Immunodominance is defined as restricted responsiveness of T cells to a few selected epitopes from complex antigens. Strategies currently used for elucidating CD4+ T cell epitopes are inadequate. To understand the mechanism of epitope selection for helper T cells, we established a cell-free antigen processing system composed of defined proteins: human leukocyte antigen-DR1 (HLA-DR1), HLA-DM and cathepsins. Our reductionist system successfully identified the physiologically selected immunodominant epitopes of two model antigens: hemagglutinin-1 (HA1) from influenza virus (A/Texas/1/77) and type II collagen (CII). When applied for identification of new epitopes from a recombinant liver-stage antigen of malaria falciparum (LSA-NRC) or HA1 from H5N1 influenza virus ('avian flu'), the system selected single epitopes from each protein that were confirmed to be immunodominant by their capacity to activate CD4+ T cells from H5N1-immunized HLA-DR1-transgenic mice and LSA-NRC-vaccinated HLA-DR1-positive human volunteers. Thus, we provide a new tool for the identification of physiologically relevant helper T cell epitopes from antigens.

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A reductionist cell-free major histocompatibility complex class II antigen processing system identifies immunodominant epitopes

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