Transcription factor networks in aged naive CD4 T cells bias lineage differentiation

With reduced thymic activity, the population of naive T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naive CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naive CD4 T-cell aging is associated with a partial loss of this unbiased multipotency. We find that naive 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 beta (TGF beta) stimulation is enhanced with age due to an upregulation of the TGF beta R3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naive 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.