Quantitative restoration of immune defense in old animals determined by naive antigen‐specific CD8 T‐cell numbers

Abstract

Older humans and animals often exhibit reduced immune responses to infection and vaccination, and this often directly correlates to the numbers and frequency of naive T (Tn) cells. We found such a correlation between reduced numbers of blood CD8+ Tn cells and severe clinical outcomes of West Nile virus (WNV) in both humans naturally exposed to, and mice experimentally infected with, WNV. To examine possible causality, we sought to increase the number of CD8 Tn cells by treating C57BL/6 mice with IL-7 complexes (IL-7C, anti-IL-7 mAb bound to IL-7), shown previously to efficiently increase peripheral T-cell numbers by homeostatic proliferation. T cells underwent robust expansion following IL-7C administration to old mice increasing the number of total T cells (>fourfold) and NS4b:H-2D b -restricted antigen-specific CD8 T cells (twofold). This improved the numbers of NS4b-specific CD8 T cells detected at the peak of the response against WNV, but not survival of WNV challenge. IL-7C-treated old animals also showed no improvement in WNV-specific effector immunity (neutralizing antibody and in vivo T-cell cytotoxicity). To test quantitative limits to which CD8 Tn cell restoration could improve protective immunity, we transferred graded doses of Ag-specific precursors into old mice and showed that injection of 5400 (but

Signaling Crosstalks Drive Generation and Regeneration of the Thymus

“…Most recently, IL-7 administration has been used in a murine model of age-related lymphopenia. Aged mice were subjected to IL-7 treatment and both numbers of CD4 and CD8 naïve T-cells in spleen and lymph nodes rose to levels similar to those observed in adult mice ( 97 ).…”

The aging of the immune system and its implications for transplantation

“…This is further highlighted by our data showing that on a cell-by-cell basis, old Tn cells are at least equivalent to adult Tn cells in responding to L. monocytogenes when adoptively transferred into young recipients, whereas adult Tn cells cannot respond well in the old environment [ 74 ]. It is therefore most likely that the main problem with Tn cells in old age lies in their numerical loss (so that only ~ 25–33% remain), a defect that can be corrected by transfers of antigen-specific T cell precursors [ 75 ]. By contrast, memory responses produced in youth and young adulthood appear to be well preserved during aging [ 69 , 76 ].…”