THYMIC AGING AND T-CELL REGENERATION

Studies of T-cell regeneration using animal models have consistently s hown the importance of the thymus for T-cell regeneration. In humans, recent studies have shown that declines in thymic T-cell regenerative capacity begins relatively early in life, resulting in a limited capac ity for T-cell regeneration by young adulthood. As a result, adult hum ans who experience profound T-cell depletion regenerate T cells primar ily via relatively inefficient thymic-independent pathways, resulting in prolonged CD4 depletion, CD4(+) and CD8(+) subset alterations, limi ted TCR repertoire diversity and a propensity for activation induced c ell death. These limitations in T-cell regeneration have significant c linical implications in the setting of HIV infection and bone marrow t ransplantation and may also contribute to immunologic abnormalities as sociated with normal aging. While the mechanisms responsible for thymi c aging are not well understood, current evidence suggests that change s within the thymus itself are primary, while age-related changes in m arrow T-cell progenitors and inhibitory factors within the extrathymic host milieu contribute to a lesser extent. The development of therapi es which can reverse thymic aging are critical for improving outcome i n clinical settings of T-cell depletion, and could potentially improve immunologic function in normal aged hosts.