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

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 tr...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research