Human Major Histocompatibility Complex (MHC) class I molecules with disulfide traps secure disease-related antigenic peptides and exclude competitor peptides

Steven M. Truscott, Xiaoli Wang, Lonnie Lybarger, William E. Biddison, Cortez McBerry, John M. Martinko, Janet M. Connolly, Gerald P. Linette, Daved H. Fremont, Ted H. Hansen, Beatriz M. Carreno

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The ongoing discovery of disease-associated epitopes detected by CD8 T cells greatly facilitates peptide-based vaccine approaches and the construction of multimeric soluble recombinant proteins (e.g. tetramers) for isolation and enumeration of antigen-specific CD8 T cells. Related to these outcomes of epitope discovery is the recent demonstration that MHC class I/peptide complexes can be expressed as single chain trimers (SCTs) with peptide, β2m and heavy chain connected by linkers to form a single polypeptide chain. Studies using clinically relevant mouse models of human disease have shown that SCTs expressed by DNA vaccination are potent stimulators of cytotoxic T lymphocytes. Their vaccine efficacy has been attributed to the fact that SCTs contain a preprocessed and preloaded peptide that is stably displayed on the cell surface. Although SCTs of HLA class I/peptide complexes have been previously reported, they have not been characterized for biochemical stability or susceptibility to exogenous peptide binding. Here we demonstrate that human SCTs remain almost exclusively intact when expressed in cells and can incorporate a disulfide trap that dramatically excludes the binding of exogenous peptides. The mechanistic and practical applications of these findings for vaccine development and T cell isolation/enumeration are discussed.

Original languageEnglish (US)
Pages (from-to)7480-7490
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number12
DOIs
StatePublished - Mar 21 2008

Fingerprint

Major Histocompatibility Complex
Disulfides
Peptides
Molecules
T-cells
Vaccines
T-Lymphocytes
Epitopes
CD8 Antigens
Subunit Vaccines
Cell Separation
Cytotoxic T-Lymphocytes
Recombinant Proteins
Vaccination
Demonstrations
Antigens
DNA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Human Major Histocompatibility Complex (MHC) class I molecules with disulfide traps secure disease-related antigenic peptides and exclude competitor peptides. / Truscott, Steven M.; Wang, Xiaoli; Lybarger, Lonnie; Biddison, William E.; McBerry, Cortez; Martinko, John M.; Connolly, Janet M.; Linette, Gerald P.; Fremont, Daved H.; Hansen, Ted H.; Carreno, Beatriz M.

In: Journal of Biological Chemistry, Vol. 283, No. 12, 21.03.2008, p. 7480-7490.

Research output: Contribution to journalArticle

Truscott, SM, Wang, X, Lybarger, L, Biddison, WE, McBerry, C, Martinko, JM, Connolly, JM, Linette, GP, Fremont, DH, Hansen, TH & Carreno, BM 2008, 'Human Major Histocompatibility Complex (MHC) class I molecules with disulfide traps secure disease-related antigenic peptides and exclude competitor peptides', Journal of Biological Chemistry, vol. 283, no. 12, pp. 7480-7490. https://doi.org/10.1074/jbc.M709935200
Truscott, Steven M. ; Wang, Xiaoli ; Lybarger, Lonnie ; Biddison, William E. ; McBerry, Cortez ; Martinko, John M. ; Connolly, Janet M. ; Linette, Gerald P. ; Fremont, Daved H. ; Hansen, Ted H. ; Carreno, Beatriz M. / Human Major Histocompatibility Complex (MHC) class I molecules with disulfide traps secure disease-related antigenic peptides and exclude competitor peptides. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 12. pp. 7480-7490.
@article{510b6fe6d9f94e008cc454f74513bc7c,
title = "Human Major Histocompatibility Complex (MHC) class I molecules with disulfide traps secure disease-related antigenic peptides and exclude competitor peptides",
abstract = "The ongoing discovery of disease-associated epitopes detected by CD8 T cells greatly facilitates peptide-based vaccine approaches and the construction of multimeric soluble recombinant proteins (e.g. tetramers) for isolation and enumeration of antigen-specific CD8 T cells. Related to these outcomes of epitope discovery is the recent demonstration that MHC class I/peptide complexes can be expressed as single chain trimers (SCTs) with peptide, β2m and heavy chain connected by linkers to form a single polypeptide chain. Studies using clinically relevant mouse models of human disease have shown that SCTs expressed by DNA vaccination are potent stimulators of cytotoxic T lymphocytes. Their vaccine efficacy has been attributed to the fact that SCTs contain a preprocessed and preloaded peptide that is stably displayed on the cell surface. Although SCTs of HLA class I/peptide complexes have been previously reported, they have not been characterized for biochemical stability or susceptibility to exogenous peptide binding. Here we demonstrate that human SCTs remain almost exclusively intact when expressed in cells and can incorporate a disulfide trap that dramatically excludes the binding of exogenous peptides. The mechanistic and practical applications of these findings for vaccine development and T cell isolation/enumeration are discussed.",
author = "Truscott, {Steven M.} and Xiaoli Wang and Lonnie Lybarger and Biddison, {William E.} and Cortez McBerry and Martinko, {John M.} and Connolly, {Janet M.} and Linette, {Gerald P.} and Fremont, {Daved H.} and Hansen, {Ted H.} and Carreno, {Beatriz M.}",
year = "2008",
month = "3",
day = "21",
doi = "10.1074/jbc.M709935200",
language = "English (US)",
volume = "283",
pages = "7480--7490",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "12",

}

TY - JOUR

T1 - Human Major Histocompatibility Complex (MHC) class I molecules with disulfide traps secure disease-related antigenic peptides and exclude competitor peptides

AU - Truscott, Steven M.

AU - Wang, Xiaoli

AU - Lybarger, Lonnie

AU - Biddison, William E.

AU - McBerry, Cortez

AU - Martinko, John M.

AU - Connolly, Janet M.

AU - Linette, Gerald P.

AU - Fremont, Daved H.

AU - Hansen, Ted H.

AU - Carreno, Beatriz M.

PY - 2008/3/21

Y1 - 2008/3/21

N2 - The ongoing discovery of disease-associated epitopes detected by CD8 T cells greatly facilitates peptide-based vaccine approaches and the construction of multimeric soluble recombinant proteins (e.g. tetramers) for isolation and enumeration of antigen-specific CD8 T cells. Related to these outcomes of epitope discovery is the recent demonstration that MHC class I/peptide complexes can be expressed as single chain trimers (SCTs) with peptide, β2m and heavy chain connected by linkers to form a single polypeptide chain. Studies using clinically relevant mouse models of human disease have shown that SCTs expressed by DNA vaccination are potent stimulators of cytotoxic T lymphocytes. Their vaccine efficacy has been attributed to the fact that SCTs contain a preprocessed and preloaded peptide that is stably displayed on the cell surface. Although SCTs of HLA class I/peptide complexes have been previously reported, they have not been characterized for biochemical stability or susceptibility to exogenous peptide binding. Here we demonstrate that human SCTs remain almost exclusively intact when expressed in cells and can incorporate a disulfide trap that dramatically excludes the binding of exogenous peptides. The mechanistic and practical applications of these findings for vaccine development and T cell isolation/enumeration are discussed.

AB - The ongoing discovery of disease-associated epitopes detected by CD8 T cells greatly facilitates peptide-based vaccine approaches and the construction of multimeric soluble recombinant proteins (e.g. tetramers) for isolation and enumeration of antigen-specific CD8 T cells. Related to these outcomes of epitope discovery is the recent demonstration that MHC class I/peptide complexes can be expressed as single chain trimers (SCTs) with peptide, β2m and heavy chain connected by linkers to form a single polypeptide chain. Studies using clinically relevant mouse models of human disease have shown that SCTs expressed by DNA vaccination are potent stimulators of cytotoxic T lymphocytes. Their vaccine efficacy has been attributed to the fact that SCTs contain a preprocessed and preloaded peptide that is stably displayed on the cell surface. Although SCTs of HLA class I/peptide complexes have been previously reported, they have not been characterized for biochemical stability or susceptibility to exogenous peptide binding. Here we demonstrate that human SCTs remain almost exclusively intact when expressed in cells and can incorporate a disulfide trap that dramatically excludes the binding of exogenous peptides. The mechanistic and practical applications of these findings for vaccine development and T cell isolation/enumeration are discussed.

UR - http://www.scopus.com/inward/record.url?scp=43149103191&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=43149103191&partnerID=8YFLogxK

U2 - 10.1074/jbc.M709935200

DO - 10.1074/jbc.M709935200

M3 - Article

C2 - 18195006

AN - SCOPUS:43149103191

VL - 283

SP - 7480

EP - 7490

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 12

ER -