Transcription factor networks in aged na？ve CD4 T cells bias lineage differentiation

With reduced thymic activity, the population of na？ve T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, na？ve CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether na？ve CD4 T‐cell aging is associated with a partial loss of this unbiased multipotency. We find that na？ve CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor β (TGFβ) stimulation is enhanced with age due to an upregulation of the TGFβR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged na？ve CD4 T cells display altered transcription factor profiles in response to T‐cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging‐associated changes in the transcription factor profile favor TH9 commitment