Atlas: A simulation approach to understanding the role of production frequency in the sharing of T cell receptors between macaques in immune responses to simian immunodeficiency virus by Vanessa Venturi

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Society for Mathematical Biology Conference
July 30 - August 2, 2008
Centre for Mathematical Medicine, Fields Institute
Toronto, Canada

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Organizing Committee: S.Sivaloganathan-Chair(Waterloo), M.Kohandel (Waterloo), I.Pressman(Carleton), F.Skinner(Toronto Western Research Inst.), H. Zhu(York)

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A simulation approach to understanding the role of production frequency in the sharing of T cell receptors between macaques in immune responses to simian immunodeficiency virus
by
Vanessa Venturi
Centre For Vascular Research, University of New South Wales, Australia
Coauthors: Hui Yee Chin (University of New South Wales, Australia) David A Price (Cardiff University School of Medicine, UK) Daniel C Douek (Vaccine Research Center, NIAID/NIH, USA) Miles P Davenport (University of New South Wales, Australia)

Abstract

The effectiveness of T cell immune responses to viruses depends largely on the diversity of T cell receptors (TCRs) expressed on the surface of individual T cells that detect viral peptides (epitopes). These TCRs are produced by a process of germline gene recombination. The enormous potential diversity of TCRs produced in the thymus greatly exceeds the number of T cells found in an individual at any given time (eg. > 10¹⁸ vs. 10¹² in a human). Thus, it is considered surprising that T cells expressing identical TCRs in different individuals are observed in a wide variety of immune responses. However, variation in the production frequencies of different TCRs is rarely taken into account. We used simulations of a random gene recombination process to demonstrate that, even with unbiased gene recombination, some TCRs can be produced more frequently than others. For example, in a random generation of 10⁷ in-frame TCR sequences some TCRs are produced 10³ times while others are rarely produced. The simulations also demonstrate that the variety of different ways that a TCR sequence can be made from the germline genes plays an important role in how efficiently it can be produced (as opposed to being produced by one or a few frequently occurring gene recombination events). We term this process ‘convergent recombination’. To test whether convergent recombination and TCR production frequency play a role in vivo, we have investigated the experimentally observed sharing of TCRs in CD8⁺ (or ‘killer’) T cell responses specific for simian immunodeficiency virus (SIV) in an outbred population of rhesus macaques. The in silico TCR production frequency was found to be a good predictor of the observed extent of sharing of TCRs between macaques in these immune responses to SIV, suggesting that the hierarchy of TCR production frequencies in the simulated repertoire is predictive of that in the observed TCR repertoire in vivo.

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Date received: May 13, 2008