CD4 + T help promotes influenza virus-specific CD8 + T cell memory by limiting metabolic dysfunction

Jolie G. Cullen, Hayley A. McQuilten, Kylie M. Quinn, Moshe Olshansky, Brendan E. Russ, Alison Morey, Sanna Wei, Julia E. Prier, Nicole L. La Gruta, Peter C. Doherty, Stephen J. Turner

Research output: Contribution to journalArticleResearchpeer-review

Abstract

There is continued interest in developing novel vaccine strategies that induce establish optimal CD8 + cytotoxic T lymphocyte (CTL) memory for pathogens like the influenza A viruses (IAVs), where the recall of IAV-specific T cell immunity is able to protect against serologically distinct IAV infection. While it is well established that CD4 + T cell help is required for optimal CTL responses and the establishment of memory, when and how CD4 + T cell help contributes to determining the ideal memory phenotype remains unclear. We assessed the quality of IAV-specific CD8 + T cell memory established in the presence or absence of a concurrent CD4 + T cell response. We demonstrate that CD4 + T cell help appears to be required at the initial priming phase of infection for the maintenance of IAV-specific CTL memory, with “unhelped” memory CTL exhibiting intrinsic dysfunction. High-throughput RNA-sequencing established that distinct transcriptional signatures characterize the helped vs. unhelped IAV-specific memory CTL phenotype, with the unhelped set showing a more “exhausted T cell” transcriptional profile. Moreover, we identify that unhelped memory CTLs exhibit defects in a variety of energetic pathways, leading to diminished spare respiratory capacity and diminished capacity to engage glycolysis upon reactivation. Hence, CD4 + T help at the time of initial priming promotes molecular pathways that limit exhaustion by channeling metabolic processes essential for the rapid recall of memory CD8 + T cells.

Original languageEnglish
Pages (from-to)4481-4488
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number10
DOIs
Publication statusPublished - 5 Mar 2019

Keywords

  • CD4 T cell
  • CD8 T cell
  • Immunological memory
  • Influenza
  • Metabolism

Cite this

Cullen, Jolie G. ; McQuilten, Hayley A. ; Quinn, Kylie M. ; Olshansky, Moshe ; Russ, Brendan E. ; Morey, Alison ; Wei, Sanna ; Prier, Julia E. ; La Gruta, Nicole L. ; Doherty, Peter C. ; Turner, Stephen J. / CD4 + T help promotes influenza virus-specific CD8 + T cell memory by limiting metabolic dysfunction. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 10. pp. 4481-4488.
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abstract = "There is continued interest in developing novel vaccine strategies that induce establish optimal CD8 + cytotoxic T lymphocyte (CTL) memory for pathogens like the influenza A viruses (IAVs), where the recall of IAV-specific T cell immunity is able to protect against serologically distinct IAV infection. While it is well established that CD4 + T cell help is required for optimal CTL responses and the establishment of memory, when and how CD4 + T cell help contributes to determining the ideal memory phenotype remains unclear. We assessed the quality of IAV-specific CD8 + T cell memory established in the presence or absence of a concurrent CD4 + T cell response. We demonstrate that CD4 + T cell help appears to be required at the initial priming phase of infection for the maintenance of IAV-specific CTL memory, with “unhelped” memory CTL exhibiting intrinsic dysfunction. High-throughput RNA-sequencing established that distinct transcriptional signatures characterize the helped vs. unhelped IAV-specific memory CTL phenotype, with the unhelped set showing a more “exhausted T cell” transcriptional profile. Moreover, we identify that unhelped memory CTLs exhibit defects in a variety of energetic pathways, leading to diminished spare respiratory capacity and diminished capacity to engage glycolysis upon reactivation. Hence, CD4 + T help at the time of initial priming promotes molecular pathways that limit exhaustion by channeling metabolic processes essential for the rapid recall of memory CD8 + T cells.",
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CD4 + T help promotes influenza virus-specific CD8 + T cell memory by limiting metabolic dysfunction. / Cullen, Jolie G.; McQuilten, Hayley A.; Quinn, Kylie M.; Olshansky, Moshe; Russ, Brendan E.; Morey, Alison; Wei, Sanna; Prier, Julia E.; La Gruta, Nicole L.; Doherty, Peter C.; Turner, Stephen J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 10, 05.03.2019, p. 4481-4488.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Cullen, Jolie G.

AU - McQuilten, Hayley A.

AU - Quinn, Kylie M.

AU - Olshansky, Moshe

AU - Russ, Brendan E.

AU - Morey, Alison

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AB - There is continued interest in developing novel vaccine strategies that induce establish optimal CD8 + cytotoxic T lymphocyte (CTL) memory for pathogens like the influenza A viruses (IAVs), where the recall of IAV-specific T cell immunity is able to protect against serologically distinct IAV infection. While it is well established that CD4 + T cell help is required for optimal CTL responses and the establishment of memory, when and how CD4 + T cell help contributes to determining the ideal memory phenotype remains unclear. We assessed the quality of IAV-specific CD8 + T cell memory established in the presence or absence of a concurrent CD4 + T cell response. We demonstrate that CD4 + T cell help appears to be required at the initial priming phase of infection for the maintenance of IAV-specific CTL memory, with “unhelped” memory CTL exhibiting intrinsic dysfunction. High-throughput RNA-sequencing established that distinct transcriptional signatures characterize the helped vs. unhelped IAV-specific memory CTL phenotype, with the unhelped set showing a more “exhausted T cell” transcriptional profile. Moreover, we identify that unhelped memory CTLs exhibit defects in a variety of energetic pathways, leading to diminished spare respiratory capacity and diminished capacity to engage glycolysis upon reactivation. Hence, CD4 + T help at the time of initial priming promotes molecular pathways that limit exhaustion by channeling metabolic processes essential for the rapid recall of memory CD8 + T cells.

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