Effect of IL-7 therapy on naive and memory T cell homeostasis in aged rhesus macaques

Aging is associated with gradual deterioration of adaptive immune function, a hallmark of which is the profound loss of naive T cells (T_N) associated with decline in thymic output and export of new cells into the peripheral T cell pool. Because the lymphotropic cytokine IL-7 plays crucial roles in both development of T_N in the thymus and T_N homeostasis in the periphery, we sought to determine the extent to which therapeutic administration of IL-7 could reverse T_N deficiency in aging rhesus macaques (RM), either by enhancement of the demonstrably reduced thymopoiesis or by peripheral T_N expansion. Our results indicate that treatment of both adult (8-15 y) and old (>20 y) RM with recombinant simian IL-7 (rsIL-7) results in only transient increases in peripheral CD4⁺ and CD8⁺ T_N numbers with no long-term benefit, even with repeated therapy. This transient effect was due to peripheral T_N expansion and not enhanced thymic function, and appeared to be limited by induction of IL-7 nonresponsiveness. However, rsIL-7 therapy had a more promising effect on the central memory T cell (T_CM) population (both CD4⁺ and CD8⁺) in adult and old RM, doubling the numbers of these cells in circulation and maintaining this larger population long term. IL-7 therapy did not reduce TCR diversity of the memory T cell compartment, suggesting that rsIL-7-induced expansion was symmetrical. Thus, although rsIL-7 failed to counter age-associated T_N loss, the ability of this therapy to expand clonotypically diverse CD4⁺ and CD8⁺ T_CM populations might potentially improve adaptive immune responsiveness in the elderly.