The effects of age on CD4 upregulation and Treg distribution in a TAChR peptide-specific immune response

Studies of age-related defects in T cell function have been complicated by the difficulty of identifying antigen-specific T cells early in the activation process. Thus, peptide-responsive T cells were identified and characterized by the upregulation of CD4, an early event following T cell receptor ligation. We focused on the Torpedo californica acetylcholine receptor (TAChR) peptide, p146-162, since responses to this peptide have been well defined in young mice. In old mice, the fine specificity of the TAChR response was preserved with age; p146-162 remained immunodominant. Yet, in vitro proliferative responses to p146-162 were diminished in a dose-dependent manner in lymph node cells (LNC) derived from old peptide-primed mice. When p146-162-specific Vβ6+CD4high T cells derived from young (2-5 months) and old (20-27 months) mice were examined, the upregulation of CD4 was maintained in old age but the frequency of Vβ6+CD4high T cells was often lower; reflecting fewer CD4+ LNC, changes in TCR repertoire selection and/or altered T cell regulation. Interestingly, Foxp3+CD25+CD4+ T regulatory cell (Treg) frequencies were elevated in the old peptide-responding populations. The Vβ6-CD4normal Treg phenotype predominated in both age groups, yet a unique "activated" CD4high Treg subpopulation was also identified. Future studies may help elucidate the potential role of these CD4high Tregs in promoting age-related immune dysfunction. Support: Myasthenia Gravis Foundation, Nathan Shock Aging Center, NIH R03 AG 14557 and San Antonio Area Foundation.