Peripheral selection rather than thymic involution explains sudden contraction in naive CD4 T-cell diversity with age

Abstract

A diverse array of T cells is required for defense against pathogens. The naive CD4 T-cell repertoire reaches its peak diversity by early human adulthood and is maintained until older age. Surprisingly, around age 70, this diversity appears to plummet abruptly. A similar qualitative pattern holds for the CD4 T memory-cell population. We used mathematical models to explore different hypotheses for how such a loss of diversity might occur. The prevailing hypotheses suggest that the loss of diversity is due to a decline in emigration of cells from the thymus or a contraction in total number of cells. Our models reject these mechanisms because they yield only a gradual and minimal decline in the repertoire instead of the observed sudden and profound decrease later in life. We propose that an abrupt decline in the repertoire could be caused by the accumulation of mutations (defined here as any cell-intrinsic heritable event) that provide a short-term fitness advantage to a small number of T-cell clones (e.g., by an increased division rate or decreased death rate), with the person as a whole incurring the long-term cost of a decreased ability to fight infections.immunosenescence | modeling

The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

“…We sampled each T cell clone i from the geometric distribution (21), with bias parameter w = 0.01. The maximum size of the T cell population was set to K = 5 3 10 5 cells, whereas the total number of possible clones was set to S = 1 3 10 3 , as in previous work (21). With these values of K and S, each clone had an average starting size of K/S = 500, corresponding to an initial number of cell divisions of log 2 (500) = 9.…”

“…Experiments suggest that e t (i) decreases exponentially with time (9,18,19). Hence, we define e t ðiÞ ¼ te 2t=T GðiÞ, with T = 33.33 yr (18) and t = 0.0017 d 21 (21). In addition, experiments indicate that the daily turnover rate of naive T cells in adult humans ranges from ∼0.1 to ∼0.2% (42)(43)(44).…”

“…with those cited above (45). Therefore, we assume that T cells are lost from the population at the average rate d t = 0.15% day 21 . T cells are also lost if they have divided .50 times, which is the Hayflick limit (22,29).…”

“…We propose that over time this dynamic will cause a chain reaction of cell loss, which will suddenly drive most T cell clones to extinction. In the following, we will demonstrate, using stochastic numerical simulations based on experimental data (18,21,22,28,29,31,38,(42)(43)(44)(45)(46)(47)(48), that this model provides a plausible explanation for the sharp decline of effective clonal diversity observed in elderly humans.…”

“…A possible explanation is that the epithelial tissue of the human thymus starts to involute at the age of ∼1 year (18), which causes the number of new T cells that are subsequently produced by the thymus to decrease exponentially with age (9,11,19). However, computer simulations show that neither this exponential decrease in the rate of thymopoeisis nor the age-associated loss of T cells (20) is sufficient to elicit a dramatic decline of effective clonal diversity (21). An alternative explanation was recently proposed (21): that certain rare mutations might arise suddenly in particular T cells and allow them to outgrow other T cells, thus contributing to a sharp decrease in overall effective clonal diversity.…”