Abstract
The size and composition of the T lymphocyte compartment is subject to strict homeostatic regulation and is remarkably stable throughout life in spite of variable dynamics in cell production and death during T cell development and immune responses. Homeostasis is achieved by careful orchestration of lymphocyte survival and cell division. New T cells are generated from the thymus and the number of peripheral T cells is regulated by controlling survival and proliferation. How these processes combine is however very complex. Thymic output increases in the first year of life and then decreases but is crucial for establishing repertoire diversity. Proliferation of new naive T cells plays a crucial role for maintaining numbers but at a potential cost to TCR repertoire diversity. A mechanistic two-compartment model of T cell homeostasis is described here that includes specific terms for thymic output, cell proliferation, and cell death of both resting and dividing cells. The model successfully predicts the homeostatic set point for T cells in adults and identifies variables that determine the total number of T cells. It also accurately predicts T cell numbers in children in early life despite rapid changes in thymic output and growth over this period.
Highlights
The naive T cell compartment in humans is generated early in development by the thymus and maintained throughout life by continued export from the thymus and cell division in the periphery
The two-compartment mathematical model presented here is based on the known biology of naive T cell homeostasis
Naive single positive CD4 T cells enter the peripheral pool from the thymus at rates ranging from 4 × 108 to 2 × 109 day−1 depending on age from 0 to 20 years, with a peak of 2 × 109 day−1 at about 1 year of age [15]
Summary
The naive T cell compartment in humans is generated early in development by the thymus and maintained throughout life by continued export from the thymus and cell division in the periphery. The naive T cell compartment is comprised of roughly 1011 cells circulating between the blood and the peripheral lymphoid organs. The size and composition (T cell receptor diversity) of the naive T cell compartment are subject to strict homeostatic regulation and are remarkably stable throughout adult life despite changing rates of cell production and death during T cell development and immune responses [2, 3]. Homeostasis is achieved by control of lymphocyte survival and cell division. Naive T cells are largely non-cycling [11] whereas homeostatic cell division plays an important role in maintaining naive T cell homeostasis in humans, where cell division is evident in the naive pool [12, 13]
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