The impact of aging and senescence on CD4 T cell differentiation

Abstract

Abstract With aging, the immune response and ability to return to homeostasis declines and the presence of senescent cells increases. In this study, we examined how aging and senescence impact Th subset differentiation during the response to influenza infection. In the lungs of aged mice during infection, there are significantly greater percentages of influenza-specific CD4 T cells expressing the transcription factor FoxP3, indicative of the regulatory CD4 T cell (Treg) subset, when compared to young. Higher levels of the cytokine TGFb, which can drive FoxP3 expression, were also found in the bronchoalveolar lavage (BAL) in these aged mice. Blocking TGFb with a neutralizing antibody reduced FoxP3 expression in lung CD4 T cells. Furthermore, treating aged mice with senolytic drugs prior to infection could reduce the percentage of FoxP3-expressing CD4 T cells as well as TGFb levels. Using an adoptive transfer model in which young CD4 T cells were transferred into aged hosts, we found that prior treatment of the aged hosts with senolytic drugs could reduce FoxP3 expression in the young donor cells, indicating that the senescent environment plays a role in aberrant Th subset differentiation. Finally, treatment with senolytic drugs induced differentiation of aged CD4 T cells to a healing Type 2 phenotype, which promotes a return to homeostasis, much like younger mice. These results suggest that senescent cells, via production of cytokines such as TGFb, have a significant impact on CD4 T cell differentiation, which could alter the outcome of an immune response and slow the return to homeostasis.