Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense

Peripheral T cell diversity is virtually constant in the young, but is invariably reduced in aged mice and humans. CD8(+) T cell clonal expansions (TCE) are the most drastic manifestation of, and possible contributors to, this reduced diversity. We show that the presence of TCE results ill reduced CD8(+), but not CD4(+), T cell diversity, and in functional inability to mobilize parts of the CD8(+) T cell repertoire affected by TCE. In the model of herpes simplex virus (HSV)-1 infection of B6 mice, >90% of the responding CD8(+) T cells use Vbeta10 or Vbeta8 and are directed against a single glycoprotein B (gB(498-505)) epitope, gB-8p. We found that old animals bearing CD8(+) TCE within Vbeta10 or Vbeta8 families failed to mount an effective immune response against HSV-1, as judged by reduced numbers of peptide-major histocompatibility complex tetramer(+) CD8 T cells and an absence of antiviral lyric function. Furthermore, Vbeta8 TCE experimentally introduced into young mice resulted in lower resistance to viral challenge, whereas Vbeta5(+) TCE induced in a similar fashion did not impact viral resistance. These results demonstrate that age-related TCE functionally impair the efficacy of antiviral CD8(+) T cell immunity in an antigen-specific manner, strongly suggesting that TCE are not the mere manifestation of, but are also a contributing factor to, the immunodeficiency of senescence.