Plenary paper Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells

The forkhead box n1 (Foxn1) transcrip-tion factor is essential for thymic organo-genesis during embryonic development; however, a functional role of Foxn1 in the postnatal thymus is less well understood. We developed Foxn1 transgenic mice (Foxn1Tg), in which overexpression of Foxn1 is driven by the human keratin-14 promoter. Expression of the Foxn1 trans-gene increased the endogenous Foxn1 levels. In aged mice, overexpression of Foxn1 in the thymus attenuated the de-cline in thymocyte numbers, prevented the decline in frequency of early thymic progenitors, and generated a higher num-ber of signal joint TCR excised circle. Histologic studies revealed that struc-tural alterations associated with thymic involution were diminished in aged Foxn1 Tg. Total numbers of EpCAM MHC II and MHC IIhi thymic epithelial cells were higher in young and old Foxn1Tg and more EpCAM MHC IIhi TEC ex-pressed Ki-67 in aged Foxn1Tg compared with WT. Furthermore, Foxn1Tg displayed a significant reduction in the expansion of splenic CD4 memory compartments and attenuated the decline in CD4 and CD8 naive compartments. Our data indicate that manipulation of Foxn1 ex-pression in the thymus ameliorates thymopoiesis in aged mice and offer a strategy to combat the age-associated decline in naive T-cell production and CD4 naive/memory ratios in the elderly. (Blood. 2011;118(22):5723-5731