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Proc Natl Acad Sci U S A. 2019 Feb 20. pii: 201808849. doi: 10.1073/pnas.1808849116. [Epub ahead of print]

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

Author information

1
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3000, Australia.
2
Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, 3800 VIC, Australia.
3
Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, 3800 VIC, Australia.
4
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3000, Australia; pcd@unimelb.edu.au stephen.j.turner@monash.edu.
5
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.

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.

KEYWORDS:

CD4 T cell; CD8+ T cell; immunological memory; influenza; metabolism

PMID:
30787194
DOI:
10.1073/pnas.1808849116

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