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156 MECHANISMS AFFECTING T-CELL PRIMING AND DIFFERENTIATION IN THE ELDERLY.
  1. W. -W. Lee,
  2. D. Cui,
  3. C. M. Weyand,
  4. J. J. Goronzy
  1. Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Atlanta, GA

Abstract

Purpose The ability to mount primary immune responses is severely compromised with age. Although thymic production of new T cells dwindles early during adulthood, size and repertoire contraction of na•ve T cells explain defective immunocompetence only after the age of 75 years. We have hypothesized that cellular defects in aged na•ve T cells impair their ability to respond and to clonally expand to activation stimuli.

Methods Purified na•ve CD45RA+CD4+ T cells from young (20 to 31 years, n = 10) and old (65 to 81 years, n = 10) were co-cultured with myeloid dendritic cells and the superantigen TSST-1 to mimic in vitro priming. The system allows for separately examining high-affinity (Vb2+ T cells) and low-affinity (Vb22 T cells) T-cell responses. Dendritic cells were derived from a young donor. Cell cycle entry and progression were monitored by CSFE staining. Cell activation and differentiation were assessed by gene array and flow cytometry.

Results T-cell activation was intact in aged na•ve T cells, even after low-affinity interaction. In the young, 87.7 6 8.8% of high-affinity and 10.5 6 3.8% of low-affinity T cells entered the cell cycle compared to 87.3 6 11.8 and 9.7 6 4.3 in the old. T cells after high-affinity activation showed a more rapid cell cycle progression; however, again, there was no age-dependent difference. Flow cytometric studies of chemokine receptors documented differentiation of primed T cells, irrespective of the age of the donor. Gene array studies allowed the identification of several differentiation pathways that were intact in the elderly. However, there was a selective defect in the regulation of several thiol systems, which was confirmed by real-time PCR in a second independent cohort of young and old individuals.

Conclusions In sharp contrast to murine studies, human na•ve T cells in the elderly are able to respond to high- and low-affinity T-cell receptor ligands, enter the cell cycle, and proliferate without significant delay in cell cycle progression, suggesting effective compensation for telomere loss. The abnormal induction of selected antioxidant thiols is a promising target to understand age-dependent immune defects.

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