Foxp3+ regulatory T-cell homeostasis quantitatively differs in murine peripheral lymph nodes and spleen

Regulatory T (Treg) cells are essential for maintaining self-tolerance and modulating inflammatory immune responses. Treg cells either develop within the thymus or are converted from CD4(+) naive T (Tnaive) cells in the periphery. The Treg-cell population size is tightly controlled and Treg-cell development and homeostasis have been intensively studied; however, quantitative information about mechanisms of peripheral Treg-cell homeostasis is lacking. Here we developed the first mathematical model of peripheral Treg-cell homeostasis, incorporating secondary lymphoid organs as separate entities and encompassing factors determining the size of the Treg-cell population, namely thymic output, homeostatic proliferation, peripheral conversion, transorgan migration, apoptosis, and the Tnaive-cell population. Quantitative data were collected by monitoring Tnaive-cell homeostasis and Treg-cell rebound after selective in vivo depletion of Treg cells. Our model predicted the previously unanticipated possibility that Treg cells regulate migration of Tnaive cells between spleen and peripheral lymph nodes (LNs), whereas migration of Treg cells between these organs can largely be neglected. Furthermore, our simulations suggested that peripheral conversion significantly contributed to the maintenance of the Treg-cell population, especially in LNs. Hence, we provide the first estimation of the peripheral Treg-cell conversion rate and propose additional facets of Treg-cell-mediated immune regulation that may previously have escaped attention.