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

Cullen, J, McQuilten, H, Quinn, K, Olshansky, M, Russ, B, Morey, A, Wei, S, Prier, J, La Gruta, N, Doherty, P and Turner, S 2019, 'CD4+ T help promotes influenza virus-specific CD8+ T cell memory by limiting metabolic dysfunction', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 10, pp. 4481-4488.


Document type: Journal Article
Collection: Journal Articles

Title CD4+ T help promotes influenza virus-specific CD8+ T cell memory by limiting metabolic dysfunction
Author(s) Cullen, J
McQuilten, H
Quinn, K
Olshansky, M
Russ, B
Morey, A
Wei, S
Prier, J
La Gruta, N
Doherty, P
Turner, S
Year 2019
Journal name Proceedings of the National Academy of Sciences of the United States of America
Volume number 116
Issue number 10
Start page 4481
End page 4488
Total pages 8
Publisher National Academy of Sciences
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.
Subject Cellular Immunology
Keyword(s) CD4 T cell
CD8 T cell
Immunological memory
Influenza
Metabolism
DOI - identifier 10.1073/pnas.1808849116
Copyright notice Copyright © 2019 National Academy of Sciences
ISSN 0027-8424
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