Abstract
The specificity of T cells is that each T cell has only one T cell receptor (TCR). A T cell clone represents a collection of T cells with the same TCR sequence. Thus, the number of different T cell clones in an organism reflects the number of different T cell receptors (TCRs) that arise from recombination of the V(D)J gene segments during T cell development in the thymus. TCR diversity and more specifically, the clone abundance distribution, are important factors in immune functions. Specific recombination patterns occur more frequently than others while subsequent interactions between TCRs and self-antigens are known to trigger proliferation and sustain naive T cell survival. These processes are TCR-dependent, leading to clone-dependent thymic export and naive T cell proliferation rates. We describe the heterogeneous steady-state population of naive T cells (those that have not yet been antigenically triggered) by using a mean-field model of a regulated birth-death-immigration process. After accounting for random sampling, we investigate how TCR-dependent heterogeneities in immigration and proliferation rates affect the shape of clone abundance distributions (the number of different clones that are represented by a specific number of cells, or “clone counts”). By using reasonable physiological parameter values and fitting predicted clone counts to experimentally sampled clone abundances, we show that realistic levels of heterogeneity in immigration rates cause very little change to predicted clone-counts, but that modest heterogeneity in proliferation rates can generate the observed clone abundances. Our analysis provides constraints among physiological parameters that are necessary to yield predictions that qualitatively match the data. Assumptions of the model and potentially other important mechanistic factors are discussed.
Highlights
Naive T cells play a crucial role in the immune system’s response to pathogens, tumors, and other infectious agents
To understand the observed clone counts, we focus on the clone count distribution ^c k associated only with naive T cells, the first type of cells produced by the thymus that have not yet been activated by any antigen
We define Q to be the theoretical number of all possible functional naive T cell receptor clones that can be generated by V(D)J recombination in the thymus which is estimated to be Q ~ 1013 – 1018 [6, 28]
Summary
Naive T cells play a crucial role in the immune system’s response to pathogens, tumors, and other infectious agents. These cells are produced in the bone marrow, mature in the thymus, circulate through the blood, and migrate to the lymph nodes where they may be presented with different antigen proteins from various pathogens. Because of the large number of unknown pathogens, TCR clonal diversity is a key factor for mounting an effective immune response. Recent studies reveal that human TCR clonal diversity is implicated in healthy aging, neonatal immunity, vaccination response and T cell reconstitution following haematopoietic stem cell transplantation [1, 2]. Model predictions are compared with T cell clone data to estimate reasonable and realistic parameter values
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