Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8T cells

Corey Smith, Diah Elhassen, Stephanie Gras, Katherine K Wynn, Vijayendra Dasari, Judy Tellam, Siok-Keen Tey, Yu Chih Liu, Jamie Rossjohn, Scott R Burrows, Rajiv Khanna

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Abstract

T-box transcription factors T-bet (Tbx21) and Eomesodermin (Eomes) are critical players in CD8(+) cytotoxic T lymphocyte effector function and differentiation but how the expression of these transcription factors is regulated remains poorly defined. Here we show that dominant T cells directed towards human cytomegalovirus (CMV), expressing significantly higher levels of T-bet with graded loss of Eomes expression (T-bet(hi)Eomes(hi/lo)), are more efficient in recognizing endogenously processed peptide-major histocompatibility complexes (pMHC) when compared to subdominant virus-specific T cells expressing lower levels of T-bet and high levels of Eomes (T-bet(int)Eomes(hi)). Paradoxically, the T-bet(hi)Eomes(hi/lo) dominant populations that efficiently recognised endogenous antigen demonstrated lower intrinsic avidity for pMHC, whilst T-bet(int)Eomes(hi) subdominant populations were characterized by higher pMHC avidity and less efficient recognition of virus-infected cells. Importantly, differential endogenous viral antigen recognition by CMV-specific CD8(+) T cells also correlated with the differentiation status and expression of perforin, granzyme B and K. Furthermore, we demonstrate that the expression of T-bet correlates with clonal expansion, differentiation status and expression of perforin, granzyme B and K in antigen-specific T cells. These findings illustrate how endogenous viral antigen presentation during persistent viral infection may influence the transcriptional program of virus-specific T cells and their functional profile in the peripheral blood of humans.
Original languageEnglish
Pages (from-to)3237-3245
Number of pages9
JournalBlood
Volume120
Issue number16
DOIs
Publication statusPublished - 2012

Cite this

Smith, Corey ; Elhassen, Diah ; Gras, Stephanie ; Wynn, Katherine K ; Dasari, Vijayendra ; Tellam, Judy ; Tey, Siok-Keen ; Liu, Yu Chih ; Rossjohn, Jamie ; Burrows, Scott R ; Khanna, Rajiv. / Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8T cells. In: Blood. 2012 ; Vol. 120, No. 16. pp. 3237-3245.
@article{76ef8448c2f84c5ab157b70fc59aa71c,
title = "Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8+ T cells",
abstract = "T-box transcription factors T-bet (Tbx21) and Eomesodermin (Eomes) are critical players in CD8(+) cytotoxic T lymphocyte effector function and differentiation but how the expression of these transcription factors is regulated remains poorly defined. Here we show that dominant T cells directed towards human cytomegalovirus (CMV), expressing significantly higher levels of T-bet with graded loss of Eomes expression (T-bet(hi)Eomes(hi/lo)), are more efficient in recognizing endogenously processed peptide-major histocompatibility complexes (pMHC) when compared to subdominant virus-specific T cells expressing lower levels of T-bet and high levels of Eomes (T-bet(int)Eomes(hi)). Paradoxically, the T-bet(hi)Eomes(hi/lo) dominant populations that efficiently recognised endogenous antigen demonstrated lower intrinsic avidity for pMHC, whilst T-bet(int)Eomes(hi) subdominant populations were characterized by higher pMHC avidity and less efficient recognition of virus-infected cells. Importantly, differential endogenous viral antigen recognition by CMV-specific CD8(+) T cells also correlated with the differentiation status and expression of perforin, granzyme B and K. Furthermore, we demonstrate that the expression of T-bet correlates with clonal expansion, differentiation status and expression of perforin, granzyme B and K in antigen-specific T cells. These findings illustrate how endogenous viral antigen presentation during persistent viral infection may influence the transcriptional program of virus-specific T cells and their functional profile in the peripheral blood of humans.",
author = "Corey Smith and Diah Elhassen and Stephanie Gras and Wynn, {Katherine K} and Vijayendra Dasari and Judy Tellam and Siok-Keen Tey and Liu, {Yu Chih} and Jamie Rossjohn and Burrows, {Scott R} and Rajiv Khanna",
year = "2012",
doi = "10.1182/blood-2012-03-420182",
language = "English",
volume = "120",
pages = "3237--3245",
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Smith, C, Elhassen, D, Gras, S, Wynn, KK, Dasari, V, Tellam, J, Tey, S-K, Liu, YC, Rossjohn, J, Burrows, SR & Khanna, R 2012, 'Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8T cells', Blood, vol. 120, no. 16, pp. 3237-3245. https://doi.org/10.1182/blood-2012-03-420182

Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8T cells. / Smith, Corey; Elhassen, Diah; Gras, Stephanie; Wynn, Katherine K; Dasari, Vijayendra; Tellam, Judy; Tey, Siok-Keen; Liu, Yu Chih; Rossjohn, Jamie; Burrows, Scott R; Khanna, Rajiv.

In: Blood, Vol. 120, No. 16, 2012, p. 3237-3245.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8+ T cells

AU - Smith, Corey

AU - Elhassen, Diah

AU - Gras, Stephanie

AU - Wynn, Katherine K

AU - Dasari, Vijayendra

AU - Tellam, Judy

AU - Tey, Siok-Keen

AU - Liu, Yu Chih

AU - Rossjohn, Jamie

AU - Burrows, Scott R

AU - Khanna, Rajiv

PY - 2012

Y1 - 2012

N2 - T-box transcription factors T-bet (Tbx21) and Eomesodermin (Eomes) are critical players in CD8(+) cytotoxic T lymphocyte effector function and differentiation but how the expression of these transcription factors is regulated remains poorly defined. Here we show that dominant T cells directed towards human cytomegalovirus (CMV), expressing significantly higher levels of T-bet with graded loss of Eomes expression (T-bet(hi)Eomes(hi/lo)), are more efficient in recognizing endogenously processed peptide-major histocompatibility complexes (pMHC) when compared to subdominant virus-specific T cells expressing lower levels of T-bet and high levels of Eomes (T-bet(int)Eomes(hi)). Paradoxically, the T-bet(hi)Eomes(hi/lo) dominant populations that efficiently recognised endogenous antigen demonstrated lower intrinsic avidity for pMHC, whilst T-bet(int)Eomes(hi) subdominant populations were characterized by higher pMHC avidity and less efficient recognition of virus-infected cells. Importantly, differential endogenous viral antigen recognition by CMV-specific CD8(+) T cells also correlated with the differentiation status and expression of perforin, granzyme B and K. Furthermore, we demonstrate that the expression of T-bet correlates with clonal expansion, differentiation status and expression of perforin, granzyme B and K in antigen-specific T cells. These findings illustrate how endogenous viral antigen presentation during persistent viral infection may influence the transcriptional program of virus-specific T cells and their functional profile in the peripheral blood of humans.

AB - T-box transcription factors T-bet (Tbx21) and Eomesodermin (Eomes) are critical players in CD8(+) cytotoxic T lymphocyte effector function and differentiation but how the expression of these transcription factors is regulated remains poorly defined. Here we show that dominant T cells directed towards human cytomegalovirus (CMV), expressing significantly higher levels of T-bet with graded loss of Eomes expression (T-bet(hi)Eomes(hi/lo)), are more efficient in recognizing endogenously processed peptide-major histocompatibility complexes (pMHC) when compared to subdominant virus-specific T cells expressing lower levels of T-bet and high levels of Eomes (T-bet(int)Eomes(hi)). Paradoxically, the T-bet(hi)Eomes(hi/lo) dominant populations that efficiently recognised endogenous antigen demonstrated lower intrinsic avidity for pMHC, whilst T-bet(int)Eomes(hi) subdominant populations were characterized by higher pMHC avidity and less efficient recognition of virus-infected cells. Importantly, differential endogenous viral antigen recognition by CMV-specific CD8(+) T cells also correlated with the differentiation status and expression of perforin, granzyme B and K. Furthermore, we demonstrate that the expression of T-bet correlates with clonal expansion, differentiation status and expression of perforin, granzyme B and K in antigen-specific T cells. These findings illustrate how endogenous viral antigen presentation during persistent viral infection may influence the transcriptional program of virus-specific T cells and their functional profile in the peripheral blood of humans.

UR - http://bloodjournal.hematologylibrary.org/content/120/16/3237.full.pdf

U2 - 10.1182/blood-2012-03-420182

DO - 10.1182/blood-2012-03-420182

M3 - Article

VL - 120

SP - 3237

EP - 3245

JO - Blood

JF - Blood

SN - 0006-4971

IS - 16

ER -