Abstract
The processes regulating peripheral naive T-cell numbers and clonal diversity remain poorly understood. Conceptually, homeostatic mechanisms must fall into the broad categories of neutral (simple random birth–death models), competition (regulation of cell numbers through quorum-sensing, perhaps via limiting shared resources), adaptation (involving cell-intrinsic changes in homeostatic fitness, defined as net growth rate over time), or selection (involving the loss or outgrowth of cell populations deriving from intercellular variation in fitness). There may also be stably maintained heterogeneity within the naive T-cell pool. To distinguish between these mechanisms, we confront very general models of these processes with an array of experimental data, both new and published. While reduced competition for homeostatic stimuli may impact cell survival or proliferation in neonates or under moderate to severe lymphopenia, we show that the only mechanism capable of explaining multiple, independent experimental studies of naive CD4+ and CD8+ T-cell homeostasis in mice from young adulthood into old age is one of adaptation, in which cells act independently and accrue a survival or proliferative advantage continuously with their post-thymic age. However, aged naive T cells may also be functionally impaired, and so the accumulation of older cells via ‘conditioning through experience’ may contribute to reduced immune responsiveness in the elderly.
Highlights
Naive T cells accumulate in the periphery rapidly from birth, but their numbers decline gradually from puberty onwards in both mice and humans due to the slow involution of thymus and associated decline in the export of new cells [1, 2]
The body maintains large populations of naive T cells, a type of white blood cell that is able to respond to pathogens. This arsenal is essential for our capacity to fight novel infections throughout our lifespan, and their numbers remain quite stable despite a gradual decline in the production of new naive T cells as we age
Despite substantial knowledge of the qualitative nature of the cues involved in their survival and proliferative renewal—which include signals through the T-cell receptor (TCR) and from cytokines—we have a relatively limited quantitative understanding of how the total numbers and receptor diversity of naive T cells are determined throughout life
Summary
Naive T cells accumulate in the periphery rapidly from birth, but their numbers decline gradually from puberty onwards in both mice and humans due to the slow involution of thymus and associated decline in the export of new cells [1, 2]. The consensus in the field has been that the population dynamics of naive T cells are influenced by intra- and/or interclonal competition for limiting homeostatic cues, largely motivated by observations that homeostatic proliferation and cell longevity increase under severely lymphopenic conditions [3,4,5,6,7]. In support of this hypothesis, mathematical models of resource competition—in which all cells compete for a limiting, ‘public’ supply of homeostatic stimuli —have successfully described naive T-cell population dynamics in lymphoreplete and partially lymphopenic settings [8, 9]. Naive TCR transgenic T cells from aged mice persist longer than the same cells from young mice following transfer, and naive T cells are lost more slowly following thymectomy in old mice than in young mice [14]
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