title: From pre-DP, post-DP, SP4, and SP8 Thymocyte Cell Counts to a Dynamical Model of Cortical and Medullary Selection.
abstract: Cells of the mature αβ T cell repertoire arise from the development in the thymus of bone marrow precursors (thymocytes). αβ T cell maturation is characterized by the expression of thousands of copies of identical αβ T cell receptors and the CD4 and/or CD8 co-receptors on the surface of thymocytes. The maturation stages of a thymocyte are: (1) double negative (DN) (TCR(-), CD4(-) and CD8(-)), (2) double positive (DP) (TCR(+), CD4(+) and CD8(+)), and (3) single positive (SP) (TCR(+), CD4(+) or CD8(+)). Thymic antigen presenting cells provide the appropriate micro-architecture for the maturation of thymocytes, which "sense" the signaling environment via their randomly generated TCRs. Thymic development is characterized by (i) an extremely low success rate, and (ii) the selection of a functional and self-tolerant T cell repertoire. In this paper, we combine recent experimental data and mathematical modeling to study the selection events that take place in the thymus after the DN stage. The stable steady state of the model for the pre-DP, post-DP, and SP populations is identified with the experimentally measured cell counts from 5.5- to 17-week-old mice. We make use of residence times in the cortex and the medulla for the different populations, as well as recently reported asymmetric death rates for CD4 and CD8 SP thymocytes. We estimate that 65.8% of pre-DP thymocytes undergo death by neglect. In the post-DP compartment, 91.7% undergo death by negative selection, 4.7% become CD4 SP, and 3.6% become CD8 SP. Death by negative selection in the medulla removes 8.6% of CD4 SP and 32.1% of CD8 SP thymocytes. Approximately 46.3% of CD4 SP and 27% of CD8 SP thymocytes divide before dying or exiting the thymus.
authors.affiliation: Department of Applied Mathematics, School of Mathematics, University of Leeds , Leeds , UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Sawicka
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota , Minneapolis, MN , USA.
authors.forename: Gretta L
authors.initials: GL
authors.lastname: Stritesky
authors.affiliation: Department of Applied Mathematics, School of Mathematics, University of Leeds , Leeds , UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Reynolds
authors.affiliation: Department of Applied Mathematics, School of Mathematics, University of Leeds , Leeds , UK.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Abourashchi
authors.affiliation: Department of Applied Mathematics, School of Mathematics, University of Leeds , Leeds , UK.
authors.forename: Grant
authors.initials: G
authors.lastname: Lythe
authors.affiliation: Department of Applied Mathematics, School of Mathematics, University of Leeds , Leeds , UK.
authors.forename: Carmen
authors.initials: C
authors.lastname: Molina-París
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota , Minneapolis, MN , USA.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Hogquist
keywords: death by neglect; mathematical model; negative selection; positive selection; steady state; thymocytes