tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A. 2019 Feb 20. pii: 201808849. doi: 10.1073/pnas.1808849116. [Epub ahead of print]
[h=1]CD4[SUP]+[/SUP] T help promotes influenza virus-specific CD8[SUP]+[/SUP] T cell memory by limiting metabolic dysfunction.[/h] Cullen JG[SUP]1[/SUP], McQuilten HA[SUP]1[/SUP], Quinn KM[SUP]2[/SUP], Olshansky M[SUP]3[/SUP], Russ BE[SUP]3[/SUP], Morey A[SUP]3[/SUP], Wei S[SUP]3[/SUP], Prier JE[SUP]1[/SUP], La Gruta NL[SUP]2[/SUP], Doherty PC[SUP]4,[/SUP][SUP]5[/SUP], Turner SJ[SUP]4,[/SUP][SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] There is continued interest in developing novel vaccine strategies that induce establish optimal CD8[SUP]+[/SUP] 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[SUP]+[/SUP] T cell help is required for optimal CTL responses and the establishment of memory, when and how CD4[SUP]+[/SUP] T cell help contributes to determining the ideal memory phenotype remains unclear. We assessed the quality of IAV-specific CD8[SUP]+[/SUP] T cell memory established in the presence or absence of a concurrent CD4[SUP]+[/SUP] T cell response. We demonstrate that CD4[SUP]+[/SUP] 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[SUP]+[/SUP] 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[SUP]+[/SUP] T cells.
[h=4]KEYWORDS:[/h] CD4 T cell; CD8+ T cell; immunological memory; influenza; metabolism
PMID: 30787194 DOI: 10.1073/pnas.1808849116
[h=1]CD4[SUP]+[/SUP] T help promotes influenza virus-specific CD8[SUP]+[/SUP] T cell memory by limiting metabolic dysfunction.[/h] Cullen JG[SUP]1[/SUP], McQuilten HA[SUP]1[/SUP], Quinn KM[SUP]2[/SUP], Olshansky M[SUP]3[/SUP], Russ BE[SUP]3[/SUP], Morey A[SUP]3[/SUP], Wei S[SUP]3[/SUP], Prier JE[SUP]1[/SUP], La Gruta NL[SUP]2[/SUP], Doherty PC[SUP]4,[/SUP][SUP]5[/SUP], Turner SJ[SUP]4,[/SUP][SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] There is continued interest in developing novel vaccine strategies that induce establish optimal CD8[SUP]+[/SUP] 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[SUP]+[/SUP] T cell help is required for optimal CTL responses and the establishment of memory, when and how CD4[SUP]+[/SUP] T cell help contributes to determining the ideal memory phenotype remains unclear. We assessed the quality of IAV-specific CD8[SUP]+[/SUP] T cell memory established in the presence or absence of a concurrent CD4[SUP]+[/SUP] T cell response. We demonstrate that CD4[SUP]+[/SUP] 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[SUP]+[/SUP] 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[SUP]+[/SUP] T cells.
[h=4]KEYWORDS:[/h] CD4 T cell; CD8+ T cell; immunological memory; influenza; metabolism
PMID: 30787194 DOI: 10.1073/pnas.1808849116