Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1/PD-L1 pathway

Celine S. Lages, Ian Lewkowich, Alyssa Sproles, Marsha Wills-Karp, Claire Chougnet

Research output: Contribution to journalArticle

Abstract

Programmed cell death-1 (PD-1) is a newly characterized negative regulator of immune responses. The interaction of PD-1 with its ligands (PD-L1 and PD-L2) inhibits T-cell proliferation and cytokine production in young mice. Increased PD-1 expression has been described during chronic infections, inducing chronic activation of the immune system to control it. As aging is associated with chronic immune activation, PD-1 may contribute to age-associated T-cell dysfunction. Our data showed the following results in aged mice: (i) the number of PD-1-expressing T cells and the level of expression of PD-Ls was increased on dendritic cell subsets and T cells; (ii) PD-1+ T cells were exhausted effector memory T cells, as shown by their lower level of CD127, CD25 and CD28, as well as their limited proliferative and cytokine-producing capacity; (iii) the expression of PD-1 was up-regulated after T-cell receptor-mediated activation of CD8+ T cells, but not of CD4+ T cells; (iv) blockade of the PD-1/PD-L1 pathway moderately improved the cytokine production of T cells from old mice but did not restore their proliferation; and (v) blockade of the PD-1/PD-L1 pathway did not restore function of PD-1+ T cells; its effect appeared to be exclusively mediated by increased functionality of the PD-1- T cells. Our data thus suggest that blockade of the PD-1/PD-L1 is not likely to be efficient at restoring exhausted T-cell responses in aged hosts, although improving the responses of PD-1- T cells may prove to be a helpful strategy in enhancing primary responses.

Original languageEnglish (US)
Pages (from-to)785-798
Number of pages14
JournalAging Cell
Volume9
Issue number5
DOIs
Publication statusPublished - Oct 2010
Externally publishedYes

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Keywords

  • Aging
  • Dendritic cells
  • Programmed cell death-1 (PD-1) ligands
  • T cells

ASJC Scopus subject areas

  • Cell Biology
  • Aging

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