Endogenous viral antigen processing generates pepvtide-specific MHC class I cell-surface clusters

Xiuju Lu, James S. Gibbs, Heather D. Hickman, Alexandre David, Brian P. Dolan, Yetao Jin, David M Kranz, Jack R. Bennink, Jonathan W. Yewdell, Rajat Varma

Research output: Contribution to journalArticle

Abstract

Sensitivity is essential in CD8+ T-cell killing of virus-infected cells and tumor cells. Although the affinity of the T-cell receptor (TCR) for antigen is relatively low, the avidity of T cell-antigen-presenting cell interactions is greatly enhanced by increasing the valence of the interaction. It is known that TCRs cluster into protein islands after engaging their cognate antigen (peptides bound to MHC molecules). Here, we show that mouse Kb class I molecules segregate into preformed, long-lasting (hours) clusters on the antigen-presenting cell surface based on their bound viral peptide. Peptide-specific Kb clustering occurs when source antigens are expressed by vaccinia or vesicular stomatitis virus, either as proteasome-liberated precursors or free intracellular peptides. By contrast, Kb-peptide complexes generated by incubating cells with synthetic peptides are extensively intermingled on the cell surface. Peptide-specific complex sorting is first detected in the Golgi complex, and compromised by removing the Kb cytoplasmic tail. Peptide-specific clustering is associated with increased T-cell sensitivity: on a per-complex basis, endogenous SIINFEKL activates T cells more efficiently than synthetic SIINFEKL, and wild-type Kb presents endogenous SIINFEKL more efficiently than tailless Kb. We propose that endogenous processing generates peptide-specific clusters of class I molecules to maximize the sensitivity and speed of T-cell immunosurveillance.

Original languageEnglish (US)
Pages (from-to)15407-15412
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number38
DOIs
StatePublished - Sep 18 2012

Fingerprint

Viral Antigens
Antigen Presentation
Peptides
T-Lymphocytes
Antigen-Presenting Cells
Cluster Analysis
Viruses
Artificial Cells
Antigens
Immunologic Monitoring
Vaccinia
Vesicular Stomatitis
Viral Tumor Antigens
Golgi Apparatus
Proteasome Endopeptidase Complex
T-Cell Antigen Receptor
Islands
Cell Communication
Tail

Keywords

  • Antigen processing/presentation
  • CD8 T cell recognition
  • Dual-color TIRF imaging
  • Intracellular trafficking
  • MHC class I clustering

ASJC Scopus subject areas

  • General

Cite this

Endogenous viral antigen processing generates pepvtide-specific MHC class I cell-surface clusters. / Lu, Xiuju; Gibbs, James S.; Hickman, Heather D.; David, Alexandre; Dolan, Brian P.; Jin, Yetao; Kranz, David M; Bennink, Jack R.; Yewdell, Jonathan W.; Varma, Rajat.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 38, 18.09.2012, p. 15407-15412.

Research output: Contribution to journalArticle

Lu, Xiuju ; Gibbs, James S. ; Hickman, Heather D. ; David, Alexandre ; Dolan, Brian P. ; Jin, Yetao ; Kranz, David M ; Bennink, Jack R. ; Yewdell, Jonathan W. ; Varma, Rajat. / Endogenous viral antigen processing generates pepvtide-specific MHC class I cell-surface clusters. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 38. pp. 15407-15412.
@article{6178769e48ec407c886c2df8925e316d,
title = "Endogenous viral antigen processing generates pepvtide-specific MHC class I cell-surface clusters",
abstract = "Sensitivity is essential in CD8+ T-cell killing of virus-infected cells and tumor cells. Although the affinity of the T-cell receptor (TCR) for antigen is relatively low, the avidity of T cell-antigen-presenting cell interactions is greatly enhanced by increasing the valence of the interaction. It is known that TCRs cluster into protein islands after engaging their cognate antigen (peptides bound to MHC molecules). Here, we show that mouse Kb class I molecules segregate into preformed, long-lasting (hours) clusters on the antigen-presenting cell surface based on their bound viral peptide. Peptide-specific Kb clustering occurs when source antigens are expressed by vaccinia or vesicular stomatitis virus, either as proteasome-liberated precursors or free intracellular peptides. By contrast, Kb-peptide complexes generated by incubating cells with synthetic peptides are extensively intermingled on the cell surface. Peptide-specific complex sorting is first detected in the Golgi complex, and compromised by removing the Kb cytoplasmic tail. Peptide-specific clustering is associated with increased T-cell sensitivity: on a per-complex basis, endogenous SIINFEKL activates T cells more efficiently than synthetic SIINFEKL, and wild-type Kb presents endogenous SIINFEKL more efficiently than tailless Kb. We propose that endogenous processing generates peptide-specific clusters of class I molecules to maximize the sensitivity and speed of T-cell immunosurveillance.",
keywords = "Antigen processing/presentation, CD8 T cell recognition, Dual-color TIRF imaging, Intracellular trafficking, MHC class I clustering",
author = "Xiuju Lu and Gibbs, {James S.} and Hickman, {Heather D.} and Alexandre David and Dolan, {Brian P.} and Yetao Jin and Kranz, {David M} and Bennink, {Jack R.} and Yewdell, {Jonathan W.} and Rajat Varma",
year = "2012",
month = "9",
day = "18",
doi = "10.1073/pnas.1208696109",
language = "English (US)",
volume = "109",
pages = "15407--15412",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "38",

}

TY - JOUR

T1 - Endogenous viral antigen processing generates pepvtide-specific MHC class I cell-surface clusters

AU - Lu, Xiuju

AU - Gibbs, James S.

AU - Hickman, Heather D.

AU - David, Alexandre

AU - Dolan, Brian P.

AU - Jin, Yetao

AU - Kranz, David M

AU - Bennink, Jack R.

AU - Yewdell, Jonathan W.

AU - Varma, Rajat

PY - 2012/9/18

Y1 - 2012/9/18

N2 - Sensitivity is essential in CD8+ T-cell killing of virus-infected cells and tumor cells. Although the affinity of the T-cell receptor (TCR) for antigen is relatively low, the avidity of T cell-antigen-presenting cell interactions is greatly enhanced by increasing the valence of the interaction. It is known that TCRs cluster into protein islands after engaging their cognate antigen (peptides bound to MHC molecules). Here, we show that mouse Kb class I molecules segregate into preformed, long-lasting (hours) clusters on the antigen-presenting cell surface based on their bound viral peptide. Peptide-specific Kb clustering occurs when source antigens are expressed by vaccinia or vesicular stomatitis virus, either as proteasome-liberated precursors or free intracellular peptides. By contrast, Kb-peptide complexes generated by incubating cells with synthetic peptides are extensively intermingled on the cell surface. Peptide-specific complex sorting is first detected in the Golgi complex, and compromised by removing the Kb cytoplasmic tail. Peptide-specific clustering is associated with increased T-cell sensitivity: on a per-complex basis, endogenous SIINFEKL activates T cells more efficiently than synthetic SIINFEKL, and wild-type Kb presents endogenous SIINFEKL more efficiently than tailless Kb. We propose that endogenous processing generates peptide-specific clusters of class I molecules to maximize the sensitivity and speed of T-cell immunosurveillance.

AB - Sensitivity is essential in CD8+ T-cell killing of virus-infected cells and tumor cells. Although the affinity of the T-cell receptor (TCR) for antigen is relatively low, the avidity of T cell-antigen-presenting cell interactions is greatly enhanced by increasing the valence of the interaction. It is known that TCRs cluster into protein islands after engaging their cognate antigen (peptides bound to MHC molecules). Here, we show that mouse Kb class I molecules segregate into preformed, long-lasting (hours) clusters on the antigen-presenting cell surface based on their bound viral peptide. Peptide-specific Kb clustering occurs when source antigens are expressed by vaccinia or vesicular stomatitis virus, either as proteasome-liberated precursors or free intracellular peptides. By contrast, Kb-peptide complexes generated by incubating cells with synthetic peptides are extensively intermingled on the cell surface. Peptide-specific complex sorting is first detected in the Golgi complex, and compromised by removing the Kb cytoplasmic tail. Peptide-specific clustering is associated with increased T-cell sensitivity: on a per-complex basis, endogenous SIINFEKL activates T cells more efficiently than synthetic SIINFEKL, and wild-type Kb presents endogenous SIINFEKL more efficiently than tailless Kb. We propose that endogenous processing generates peptide-specific clusters of class I molecules to maximize the sensitivity and speed of T-cell immunosurveillance.

KW - Antigen processing/presentation

KW - CD8 T cell recognition

KW - Dual-color TIRF imaging

KW - Intracellular trafficking

KW - MHC class I clustering

UR - http://www.scopus.com/inward/record.url?scp=84866544100&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866544100&partnerID=8YFLogxK

U2 - 10.1073/pnas.1208696109

DO - 10.1073/pnas.1208696109

M3 - Article

VL - 109

SP - 15407

EP - 15412

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 38

ER -