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.

Mladen Jergović,Kristin R Renkema,Megan J Smithey,Janko Nikolich-Žugich,Heather L Thompson

doi:10.3389/fimmu.2019.02206

Mladen Jergović, Kristin R Renkema + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2019.02206

Copy DOI

Abstract

In response to infection with intracellular microorganisms, old mice mobilize decreased numbers of antigen-specific CD8 T cells with reduced expression of effector molecules and impaired cytolytic activity. Molecular mechanisms behind these defects and the cell-intrinsic (affecting naïve CD8 T cells themselves) vs. extrinsic, microenvironmental origin of such defects remain unclear. Using reciprocal transfer experiments of highly purified naïve T cells from adult and old transgenic OT-1 mice, we decisively show that the dominant effect is cell-extrinsic. Naïve 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 naïve CD8 T 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 naïve CD8 T cells and improve immune defense against intracellular microorganisms.

Highlights

Infectious diseases remain amongst the leading causes of death in older adults who often exhibit suboptimal responses to vaccination [1]
Upon primary challenge with intracellular infections, older individuals exhibit exacerbated disease symptoms and decreased survival [42]. We have shown this to be in part due to decreased absolute numbers of Ag-specific CD8 T cells responding to infection, as well as decreased CD8 T cell production of cytokines and cytotoxic killing [9, 11], consistent with results obtained by others with influenza virus [43]
We found that T-bet expression and glucose uptake were reduced in old CD8 T cells, and both of these processes stand upstream of decreased effector molecule production and terminal differentiation, as previously suggested [30]

Summary

INTRODUCTION

Infectious diseases remain amongst the leading causes of death in older adults who often exhibit suboptimal responses to vaccination [1]. We lack information on how this control may change with aging and how the activation-induced signaling cascades and transcriptional pathways interact with cell metabolic processes in old T cells. This is important because these metabolic pathways are critically involved in naïve T cell activation, and in regulation of longevity, health span [15] and immunological memory [16]. We expand on these findings and show that both the expansion and differentiation defects of CD8 T cells in aged mice could be reconstituted to the levels observed in adult mice, using specific cytokine treatments

RESULTS

DISCUSSION

EXPERIMENTAL PROCEDURES

ETHICS STATEMENT