Defective Transcriptional Programming of Effector CD8 T Cells in Aged Mice Is Cell-Extrinsic and Can Be Corrected by Administration of IL-12 and IL-18
Thompson, Heather L.
Renkema, Kristin R.
Smithey, Megan J.
AffiliationUniv Arizona, Dept Immunobiol, Coll Med Tucson
Univ Arizona, Ctr Aging, Coll Med Tucson
MetadataShow full item record
PublisherFRONTIERS MEDIA SA
CitationJergović M, Thompson HL, Renkema KR, Smithey MJ and Nikolich-Žugich J (2019) Defective Transcriptional Programming of Effector CD8 T Cells in Aged Mice Is Cell-Extrinsic and Can Be Corrected by Administration of IL-12 and IL-18. Front. Immunol. 10:2206. doi: 10.3389/fimmu.2019.02206
JournalFRONTIERS IN IMMUNOLOGY
Rights© 2019 Jergović, Thompson, Renkema, Smithey and Nikolich-Žugich. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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AbstractIn response to infection with intracellular microorganisms, old mice mobilize decreased numbers of antigen-specific CD8T cells with reduced expression of effector molecules and impaired cytolytic activity. Molecular mechanisms behind these defects and the cell-intrinsic (affecting naive CD8 T cells themselves) vs. extrinsic, microenvironmental origin of such defects remain unclear. Using reciprocal transfer experiments of highly purified naive T cells from adult and old transgenic OT-1 mice, we decisively show that the dominant effect is cell-extrinsic. Naive adult OT-1 T cells failed to expand and terminally differentiate in the old organism infected with Listeria-OVA. This defect was preceded by blunted expression of the master transcription factor T-bet and impaired glycolytic switch when T cells are primed in the old organism. However, both old and adult naive CD8T cells proliferated and produced effector molecules to a similar extent when stimulated in vitro with polyclonal stimuli, as well as when transferred into adult recipients. Multiple inflammatory cytokines with direct effects on T cell effector differentiation were decreased in spleens of old animals, particularly IL-12 and IL-18. Of note, in vivo treatment of mice with IL-12 and IL-18 on days 4-6 of Listeria infection reconstituted cytotoxic T cell response of aged mice to the level of adult. Therefore, critical cytokine signals which are underproduced in the old priming environment can restore proper transcriptional programming of old naive CD8T cells and improve immune defense against intracellular microorganisms.
NoteOpen access journal
VersionFinal published version
SponsorsUSPHSUnited States Public Health Service [U54 AI081680]; National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIH/NIAID HHSN27220110017C]