Overmaturation as a major trajectory of naive CD4 T cell aging

Aging is associated with progressive changes of cellular functional states, but whether these changes arise from novel programs or from distortion of normal developmental trajectories often remains unclear. Here, we investigate this question in the context of human immune aging by analyzing age-associated changes in CD4 T cells at single-cell resolution. We show that CD4 T cell subsets accumulate senescence-associated features at different rates and that the naive CD4 T cell compartment is highly heterogeneous with respect to senescence markers. Strikingly, transcriptional changes associated with aging of naive CD4 T cells parallel those observed during normal post-thymic maturation from recent thymic emigrants (RTE) to mature naive cells. This similarity defines a transcriptional aging trajectory that we term overmaturation, characterized by exaggerated execution of a physiological maturation program. This overmaturation is consequential for T cell function, as we demonstrate through perturbation of transcription factor TOX, which is predominantly expressed in RTE and whose expression decreases with age. Together, our findings identify transcriptional overmaturation as a major trajectory of naive CD4 T cell aging and suggest that aging-associated distortion of developmental programs can strongly contribute to immunosenescence.