Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity

Shirley G K Seah, Emma M Carrington, Wy Ching Ng, Gabrielle T Belz, Jamie L Brady, Robyn M Sutherland, Manuela S Hancock, Nicole L. La Gruta, Lorena Elizabeth Brown, Stephen J. Turner, Yifan Zhan, Andrew M Lew

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The importance of costimulation on CD4+ T cells has been well documented. However, primary CTLs against many infections including influenza can be generated in the absence of CD4+ T-cell help. The role of costimulation under such "helpless" circumstances is not fully elucidated. Here, we investigated such a role for CD28 using CTLA4Ig transgenic (Tg) mice. To ensure valid comparison across the genotypes, we showed that all mice had similar naïve precursor frequencies and similar peak viral loads. In the absence of help, viral clearance was significantly reduced in CTLA4Ig Tg mice compared with WT mice. CD44+BrdU+influenza-specific CD8+ T cells were diminished in CTLA4Ig Tg mice at days 5 and 8 postinfection. Adoptive transfer of ovalbumin-specific transgenic CD8+ T cells (OT-I)-I cells into WT or CTLA4Ig Tg mice revealed that loss of CD28 costimulation resulted in impairment in OT-I cell division. As shown previously, neither viral clearance nor the generation of influenza-specific CD8+ T cells was affected by the absence of CD4+ T cells alone. In contrast, both were markedly impaired by CD28 blockade of "helpless" CD8+ T cells. We suggest that direct CD28 costimulation of CD8+ T cells is more critical in their priming during primary influenza infection than previously appreciated.

Original languageEnglish
Pages (from-to)1744-1754
Number of pages11
JournalEuropean Journal of Immunology
Volume42
Issue number7
DOIs
Publication statusPublished - Jul 2012
Externally publishedYes

Keywords

  • CD8 T cells
  • Costimulatory molecules
  • Transgenic models
  • Virology

Cite this

Seah, S. G. K., Carrington, E. M., Ng, W. C., Belz, G. T., Brady, J. L., Sutherland, R. M., ... Lew, A. M. (2012). Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity. European Journal of Immunology, 42(7), 1744-1754. https://doi.org/10.1002/eji.201142211
Seah, Shirley G K ; Carrington, Emma M ; Ng, Wy Ching ; Belz, Gabrielle T ; Brady, Jamie L ; Sutherland, Robyn M ; Hancock, Manuela S ; La Gruta, Nicole L. ; Brown, Lorena Elizabeth ; Turner, Stephen J. ; Zhan, Yifan ; Lew, Andrew M. / Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity. In: European Journal of Immunology. 2012 ; Vol. 42, No. 7. pp. 1744-1754.
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title = "Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity",
abstract = "The importance of costimulation on CD4+ T cells has been well documented. However, primary CTLs against many infections including influenza can be generated in the absence of CD4+ T-cell help. The role of costimulation under such {"}helpless{"} circumstances is not fully elucidated. Here, we investigated such a role for CD28 using CTLA4Ig transgenic (Tg) mice. To ensure valid comparison across the genotypes, we showed that all mice had similar na{\"i}ve precursor frequencies and similar peak viral loads. In the absence of help, viral clearance was significantly reduced in CTLA4Ig Tg mice compared with WT mice. CD44+BrdU+influenza-specific CD8+ T cells were diminished in CTLA4Ig Tg mice at days 5 and 8 postinfection. Adoptive transfer of ovalbumin-specific transgenic CD8+ T cells (OT-I)-I cells into WT or CTLA4Ig Tg mice revealed that loss of CD28 costimulation resulted in impairment in OT-I cell division. As shown previously, neither viral clearance nor the generation of influenza-specific CD8+ T cells was affected by the absence of CD4+ T cells alone. In contrast, both were markedly impaired by CD28 blockade of {"}helpless{"} CD8+ T cells. We suggest that direct CD28 costimulation of CD8+ T cells is more critical in their priming during primary influenza infection than previously appreciated.",
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Seah, SGK, Carrington, EM, Ng, WC, Belz, GT, Brady, JL, Sutherland, RM, Hancock, MS, La Gruta, NL, Brown, LE, Turner, SJ, Zhan, Y & Lew, AM 2012, 'Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity', European Journal of Immunology, vol. 42, no. 7, pp. 1744-1754. https://doi.org/10.1002/eji.201142211

Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity. / Seah, Shirley G K; Carrington, Emma M; Ng, Wy Ching; Belz, Gabrielle T; Brady, Jamie L; Sutherland, Robyn M; Hancock, Manuela S; La Gruta, Nicole L.; Brown, Lorena Elizabeth; Turner, Stephen J.; Zhan, Yifan; Lew, Andrew M.

In: European Journal of Immunology, Vol. 42, No. 7, 07.2012, p. 1744-1754.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity

AU - Seah, Shirley G K

AU - Carrington, Emma M

AU - Ng, Wy Ching

AU - Belz, Gabrielle T

AU - Brady, Jamie L

AU - Sutherland, Robyn M

AU - Hancock, Manuela S

AU - La Gruta, Nicole L.

AU - Brown, Lorena Elizabeth

AU - Turner, Stephen J.

AU - Zhan, Yifan

AU - Lew, Andrew M

PY - 2012/7

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N2 - The importance of costimulation on CD4+ T cells has been well documented. However, primary CTLs against many infections including influenza can be generated in the absence of CD4+ T-cell help. The role of costimulation under such "helpless" circumstances is not fully elucidated. Here, we investigated such a role for CD28 using CTLA4Ig transgenic (Tg) mice. To ensure valid comparison across the genotypes, we showed that all mice had similar naïve precursor frequencies and similar peak viral loads. In the absence of help, viral clearance was significantly reduced in CTLA4Ig Tg mice compared with WT mice. CD44+BrdU+influenza-specific CD8+ T cells were diminished in CTLA4Ig Tg mice at days 5 and 8 postinfection. Adoptive transfer of ovalbumin-specific transgenic CD8+ T cells (OT-I)-I cells into WT or CTLA4Ig Tg mice revealed that loss of CD28 costimulation resulted in impairment in OT-I cell division. As shown previously, neither viral clearance nor the generation of influenza-specific CD8+ T cells was affected by the absence of CD4+ T cells alone. In contrast, both were markedly impaired by CD28 blockade of "helpless" CD8+ T cells. We suggest that direct CD28 costimulation of CD8+ T cells is more critical in their priming during primary influenza infection than previously appreciated.

AB - The importance of costimulation on CD4+ T cells has been well documented. However, primary CTLs against many infections including influenza can be generated in the absence of CD4+ T-cell help. The role of costimulation under such "helpless" circumstances is not fully elucidated. Here, we investigated such a role for CD28 using CTLA4Ig transgenic (Tg) mice. To ensure valid comparison across the genotypes, we showed that all mice had similar naïve precursor frequencies and similar peak viral loads. In the absence of help, viral clearance was significantly reduced in CTLA4Ig Tg mice compared with WT mice. CD44+BrdU+influenza-specific CD8+ T cells were diminished in CTLA4Ig Tg mice at days 5 and 8 postinfection. Adoptive transfer of ovalbumin-specific transgenic CD8+ T cells (OT-I)-I cells into WT or CTLA4Ig Tg mice revealed that loss of CD28 costimulation resulted in impairment in OT-I cell division. As shown previously, neither viral clearance nor the generation of influenza-specific CD8+ T cells was affected by the absence of CD4+ T cells alone. In contrast, both were markedly impaired by CD28 blockade of "helpless" CD8+ T cells. We suggest that direct CD28 costimulation of CD8+ T cells is more critical in their priming during primary influenza infection than previously appreciated.

KW - CD8 T cells

KW - Costimulatory molecules

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