Collaborative Research: Understanding generation, maintenance and dynamics of immune diversity via clone-count models

Key components of the adaptive immune system of vertebrates are B cells and T cells, lymphocytes that mediate expression of antibodies and other cells to clear pathogens from a host. Each B or T cell expresses only a single variant of its receptor but genetic recombination during development generates cells with many different receptors allowing the organism to respond to broad classes of antigens. Cells carrying one of these receptor types belong to a ?clonotype,? an ?immunotype,? or simply a ?clone.? How the diverse repertoire of lymphocyte receptors is generated, maintained, and evolves under different conditions is a fundamental multiscale problem an organism faces. Very recent high-throughput-sequencing (HTS) studies have been used to enumerate clone populations in samples drawn from different organisms in different stages of life and under different conditions and disease states. These new experiments provide a wealth of data and an opportunity to gain additional insight into the mechanisms generating and maintaining the repertoire of B cell or T cell receptors (BCRs and TCRs). In this proposal, we will systematically develop an unconventional clone-count model to describe BCR/TCR diversity. Our starting point will be homogeneous ?neutral? population models which we will adapt to describe observed clone size distributions. We will develop two different mathematical representations (cell count and clone count) within both deterministic and stochastic models. The effects of lymphocyte activation, regulation, time dependence, and sampling effects on the predicted clone size distributions will be investigated and compared with features seen in recently available data. Questions our modeling and comparison with data will address include: (i) What kinetic factors affect the steady-state clone size distributions? (ii) How do clone size distributions varying across different lymphocyte types? (iii) How do measures of clonotype diversity change with age and decreased T cell output by the thymus? (iv) Can ?public? and ?private? clonotypes be described by heterogeneity in lymphocyte production rates? (v) How do small sample fractions influence the observed clone size distributions?