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.
Highlights
T cells are a major component of the adaptive immune system that play a crucial role in protection against a wide variety of pathogens
A FIRST MODEL OF THYMIC DEVELOPMENT AFTER THE double negative (DN) STAGE we introduce a deterministic model of thymocyte development after the DN stage
Our preliminary results support the unexpectedly high death rate in the post-double positive (DP) thymocyte population observed in Ref. [21]
Summary
T cells are a major component of the adaptive immune system that play a crucial role in protection against a wide variety of pathogens. Since MHC molecules are highly polymorphic, useful T cells must be selected for in each individual of the species These T cells must have lineage specific effector functions that may include direct lysis, production of cytokines, and ability to regulate immune responses. Some T cells have the potential to drive dangerous autoimmune responses [1] For all of these reasons, the development of a T cell repertoire is a highly specialized and tightly regulated process [2, 3]. It takes place in a dedicated organ, the thymus, where unique properties of the microenvironment ensure the production of functional, yet self-tolerant T cells [4,5,6]
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