Stimulation of naive CD8+ T cells by a variant viral epitope induces activation and enhanced apoptosis

Rebecca M. Ream, Jie Sun, Thomas J. Braciale

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Classically, naive T cells recognize a specific peptide-MHC complex resulting in their activation and differentiation. However, it is known that T cells also have the ability to interact productively with variant ligands, indicating a flexibility in TCR Ag recognition. These altered peptide ligands have been shown to trigger responses ranging from complete activation to full inhibition of T cell responses, and thus may play an important role in initiating or sustaining T cell-mediated immunity. We have found that influenza virus-specific CD8+ TCR transgenic T cells differentially respond to a native (agonist) and variant viral epitope, differing in two amino acids that are thought to alter TCR recognition. In response to stimulation with the agonist epitope, these cells activate, proliferate, and differentiate into effector CTLs. Conversely, stimulation with the variant epitope results in activation, proliferation, and development of effector activity followed by rapid and extensive apoptotic cell death. Stimulation of the T cells with the altered ligand results in an inability to sustain the expression of the prosurvival molecules, Bcl-2 and Bcl-xL. These data suggest that the response to the agonist and variant epitopes may reflect TCR avidity-dependent differential signaling through the TCR, resulting either in activation-dependent T cell proliferative expansion and survival or in the accelerated death of acutely activated differentiating T cells. This process of CD8+ T cell activation, proliferation, and differentiation followed by rapid cell death may represent a novel mechanism of altered peptide ligand-induced apoptosis programmed by initial Ag receptor engagement.

Original languageEnglish (US)
Pages (from-to)2401-2409
Number of pages9
JournalJournal of Immunology
Volume184
Issue number5
DOIs
StatePublished - Mar 1 2010
Externally publishedYes

Fingerprint

Epitopes
Apoptosis
T-Lymphocytes
Ligands
Peptides
Cell Death
Orthomyxoviridae
Cellular Immunity
Cell Differentiation
Cell Proliferation
Amino Acids

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Stimulation of naive CD8+ T cells by a variant viral epitope induces activation and enhanced apoptosis. / Ream, Rebecca M.; Sun, Jie; Braciale, Thomas J.

In: Journal of Immunology, Vol. 184, No. 5, 01.03.2010, p. 2401-2409.

Research output: Contribution to journalArticle

@article{08edcfbe3a9e469daf53900b8a220d69,
title = "Stimulation of naive CD8+ T cells by a variant viral epitope induces activation and enhanced apoptosis",
abstract = "Classically, naive T cells recognize a specific peptide-MHC complex resulting in their activation and differentiation. However, it is known that T cells also have the ability to interact productively with variant ligands, indicating a flexibility in TCR Ag recognition. These altered peptide ligands have been shown to trigger responses ranging from complete activation to full inhibition of T cell responses, and thus may play an important role in initiating or sustaining T cell-mediated immunity. We have found that influenza virus-specific CD8+ TCR transgenic T cells differentially respond to a native (agonist) and variant viral epitope, differing in two amino acids that are thought to alter TCR recognition. In response to stimulation with the agonist epitope, these cells activate, proliferate, and differentiate into effector CTLs. Conversely, stimulation with the variant epitope results in activation, proliferation, and development of effector activity followed by rapid and extensive apoptotic cell death. Stimulation of the T cells with the altered ligand results in an inability to sustain the expression of the prosurvival molecules, Bcl-2 and Bcl-xL. These data suggest that the response to the agonist and variant epitopes may reflect TCR avidity-dependent differential signaling through the TCR, resulting either in activation-dependent T cell proliferative expansion and survival or in the accelerated death of acutely activated differentiating T cells. This process of CD8+ T cell activation, proliferation, and differentiation followed by rapid cell death may represent a novel mechanism of altered peptide ligand-induced apoptosis programmed by initial Ag receptor engagement.",
author = "Ream, {Rebecca M.} and Jie Sun and Braciale, {Thomas J.}",
year = "2010",
month = "3",
day = "1",
doi = "10.4049/jimmunol.0902448",
language = "English (US)",
volume = "184",
pages = "2401--2409",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "5",

}

TY - JOUR

T1 - Stimulation of naive CD8+ T cells by a variant viral epitope induces activation and enhanced apoptosis

AU - Ream, Rebecca M.

AU - Sun, Jie

AU - Braciale, Thomas J.

PY - 2010/3/1

Y1 - 2010/3/1

N2 - Classically, naive T cells recognize a specific peptide-MHC complex resulting in their activation and differentiation. However, it is known that T cells also have the ability to interact productively with variant ligands, indicating a flexibility in TCR Ag recognition. These altered peptide ligands have been shown to trigger responses ranging from complete activation to full inhibition of T cell responses, and thus may play an important role in initiating or sustaining T cell-mediated immunity. We have found that influenza virus-specific CD8+ TCR transgenic T cells differentially respond to a native (agonist) and variant viral epitope, differing in two amino acids that are thought to alter TCR recognition. In response to stimulation with the agonist epitope, these cells activate, proliferate, and differentiate into effector CTLs. Conversely, stimulation with the variant epitope results in activation, proliferation, and development of effector activity followed by rapid and extensive apoptotic cell death. Stimulation of the T cells with the altered ligand results in an inability to sustain the expression of the prosurvival molecules, Bcl-2 and Bcl-xL. These data suggest that the response to the agonist and variant epitopes may reflect TCR avidity-dependent differential signaling through the TCR, resulting either in activation-dependent T cell proliferative expansion and survival or in the accelerated death of acutely activated differentiating T cells. This process of CD8+ T cell activation, proliferation, and differentiation followed by rapid cell death may represent a novel mechanism of altered peptide ligand-induced apoptosis programmed by initial Ag receptor engagement.

AB - Classically, naive T cells recognize a specific peptide-MHC complex resulting in their activation and differentiation. However, it is known that T cells also have the ability to interact productively with variant ligands, indicating a flexibility in TCR Ag recognition. These altered peptide ligands have been shown to trigger responses ranging from complete activation to full inhibition of T cell responses, and thus may play an important role in initiating or sustaining T cell-mediated immunity. We have found that influenza virus-specific CD8+ TCR transgenic T cells differentially respond to a native (agonist) and variant viral epitope, differing in two amino acids that are thought to alter TCR recognition. In response to stimulation with the agonist epitope, these cells activate, proliferate, and differentiate into effector CTLs. Conversely, stimulation with the variant epitope results in activation, proliferation, and development of effector activity followed by rapid and extensive apoptotic cell death. Stimulation of the T cells with the altered ligand results in an inability to sustain the expression of the prosurvival molecules, Bcl-2 and Bcl-xL. These data suggest that the response to the agonist and variant epitopes may reflect TCR avidity-dependent differential signaling through the TCR, resulting either in activation-dependent T cell proliferative expansion and survival or in the accelerated death of acutely activated differentiating T cells. This process of CD8+ T cell activation, proliferation, and differentiation followed by rapid cell death may represent a novel mechanism of altered peptide ligand-induced apoptosis programmed by initial Ag receptor engagement.

UR - http://www.scopus.com/inward/record.url?scp=77951929316&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951929316&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.0902448

DO - 10.4049/jimmunol.0902448

M3 - Article

C2 - 20139280

AN - SCOPUS:77951929316

VL - 184

SP - 2401

EP - 2409

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 5

ER -