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. 2014 Feb 14:5:19.
doi: 10.3389/fimmu.2014.00019. eCollection 2014.

From pre-DP, post-DP, SP4, and SP8 Thymocyte Cell Counts to a Dynamical Model of Cortical and Medullary Selection

Maria Sawicka  1 , Gretta L Stritesky  2 , Joseph Reynolds  1 , Niloufar Abourashchi  1 , Grant Lythe  1 , Carmen Molina-París  1 , Kristin A Hogquist  2
Affiliations

From pre-DP, post-DP, SP4, and SP8 Thymocyte Cell Counts to a Dynamical Model of Cortical and Medullary Selection

Maria Sawicka et al. Front Immunol. .

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.

Keywords: death by neglect; mathematical model; negative selection; positive selection; steady state; thymocytes.

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Figures

Figure 1
Figure 1
Thymic development as hypothesized in the first model. The flux, ϕ, represents the differentiation of DNs into pre-DPs. Pre-DP thymocytes have two fates: further differentiation into the post-DP pool (φ1) or death by neglect (μ1). Post-DP thymocytes have two fates: further differentiation into the SP pool (φ2) or death by apoptosis (μ2). Finally, SP thymocytes have three fates: maturation and exit into the periphery (φ3), death by apoptosis (μ3), or proliferation (λ3).
Figure 2
Figure 2
Thymic development as hypothesized in the second model. We assume there is a flux, ϕ, that represents the differentiation of DNs into pre-DPs. Pre-DP thymocytes have two fates: further differentiation into the post-DP pool (φ1) or death by neglect (μ1). Post-DP thymocytes have three fates: further differentiation into the SP pool as CD4 SPs (φ4), or CD8 SPs (φ8), or death by apoptosis (μ2). Finally, CD4 or CD8 SP thymocytes have three fates: maturation and exit into the periphery (ξ4) or (ξ8), death by apoptosis (μ4) or (μ8), or proliferation (λ4) or (λ8).
Figure 3
Figure 3
Linear regression plots for the first model.
Figure 4
Figure 4
Linear regression plots for the second model.
Figure 5
Figure 5
Time evolution of the thymocyte populations in the second model. The different trajectories correspond to the parameter values and ranges described in Table 2.
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