The influence of three-dimensional structure on na?ve T cell homeostasis and aging

A breakdown in cellular homeostasis is thought to drive naive T cell aging, however the link between naive T cell homeostasis and aging in humans is poorly understood. To better address this, we developed a lymphoid organoid system that maintains resting naive T cells for more than 2 weeks, in conjunction with high CD45RA expression. Deep phenotypic characterization of naive T cells across age identified reduced CD45RA density as a hallmark of aging. A conversion from CD45RAhigh naive cells to a CD45RAlow phenotype was reproduced within our organoid system by structural breakdown, but not by stromal cell aging or reduced lymphocyte density, and mediated by alternative CD45 splicing. Together, these data suggest that external influences within the lymph node microenvironment may cause phenotypic conversion of naive T cells in older adults.