Phenotypical and functional analysis of peripheral T cells in foxn1 transgenic mice: Effects of aging

The thymus is the primary organ for the development and production of TCRalphabeta naive T cells. However, with increasing age thymic involution occurs, causing a decline in the output of naive T cells. The decline in naive T cell production results in a contraction in the peripheral naive and expansion of the memory T cell pools. Not only are the production and compositions of peripheral T cells altered with age, T cell functions such as T cell proliferation and production of cytokines required for cell proliferation are also declined. Currently, it is not known if restoring the decline in the production of naive T cells in aged animals would affect the peripheral T cell pools and their functions. In a mouse model, in which the transcription factor Foxn1 is over expressed under the regulation of the keratin 14 promoter, age-associated decline in the number of thymocytes is attenuated. Using the Foxn1 transgenic mouse model, we hypothesized that attenuation of thymic involution would prevent the age-associated decline in the naive T pool and T cell functions. We first determined if over expression of Foxn1 in the thymus prevents the age-associated decrease in the number of peripheral naive T cells. In comparison to aged wild type mice, the number of CD8+ naive T cells in Foxn1 transgenic mice is not reduced with age and is equivalent to that found in the young wild type and young transgenic mice. In contrast, the number of CD4+ naive T cells declines with age in Foxn1 transgenic mice, as seen in wild type mice. However, the number of CD4+ naive T cells in aged Foxn1 transgenic mice is 3.5 fold higher as compared to that in aged wild type mice. We next determined if Foxn1 transgenic mice demonstrated an age-related increase in the numbers of CD4+ and CD8+ memory T cells. In contrast to the naive T cell pool, over expression of Foxn1 in aged mice does not prevent age-associated expansion of CD4+ and CD8+ memory T cells. While both wild type and Foxn1 transgenic mice show an age-related decrease in the number of total CD4+ T cells, the number of total CD8 + T cells does not change with age in Foxn1 transgenic mice as compared to wild type mice. We also determined if over expression of Foxn1 alters the decline in T cell functions with age. As previously shown, wild type mice demonstrated an age-related decrease in IL-2 production and CD4+ T cell proliferation. Similarly, IL-2 production and CD4+ T cell proliferation were also reduced with age in Foxn1 transgenic mice. Yet, CD8+ T cell proliferation did not change with age in wild type or Foxn1 transgenic mice. Surprisingly, T cells from young Foxn1 transgenic mice showed lower IL-2 production and CD4+ and CD8+ T cell proliferation upon activation as compared to T cells from young wild type mice. The reduction in T cell functions demonstrated by both aged wild type, young and aged Foxn1 transgenic mice could be due to the decrease in CD3 expression. These data demonstrate that maintaining the production of naive T cells does not affect age-associated expansion of the memory T cell pool and suggest that there are factors other than thymic production of naive T cells that alter the peripheral memory T cell compartments and T cell functional responses in aged mice.