Functional T cells are capable of supernumerary cell division and longevity [ATAC-seq]

Differentiated somatic mammalian cells putatively exhibit species-specific division limits that impede cancer but may constrain lifespans. To provide immunity, transiently stimulated CD8 T cells undergo unusually rapid bursts of numerous cell divisions, then form quiescent long-lived memory cells that remain poised to reproliferate in response to subsequent immunological challenges. Here, we addressed whether T cells are intrinsically constrained by chronological or cell division limits. We activated mouse T cells in vivo using acute heterologous-prime-boost-boost vaccinations, transferred expanded cells to new mice, and then repeated that process iteratively. Over a period of 10 years (greatly exceeding the mouse lifespan) and 51 successive immunizations, T cells remained competent to respond to vaccination. Cells did require sufficient rest between stimulation events. Despite demonstrating the potential to expand the starting population at least 10^40-fold, cells did not show loss of proliferation control and results were not due to contamination with young cells. Persistent stimulation by chronic infections or cancer can result in a well-described transcriptional program that results in T cell proliferative senescence, functional exhaustion, and death. We found that while iterative acute stimulations also induced sustained expression and epigenetic remodeling of common exhaustion markers, including PD-1 and Tox, these cells retained the capacity to proliferate, execute antimicrobial functions, and form quiescent memory cells. These observations provide a model to better understand memory cell differentiation, exhaustion, and aging, and show that functionally competent T cells can retain the potential for extraordinary population expansion and longevity well beyond their organismal lifespan. Overall design: Chromosomal accessibility profiles of sorted N-specific memory T cells upon 1,3,6,9,18,27,30,39, and 45 immunizations