title: A minimum of two distinct heritable factors are required to explain correlation structures in proliferating lymphocytes.
abstract: During the adaptive immune response, lymphocyte populations undergo a characteristic three-phase process: expansion through a series of cell divisions; cessation of expansion; and, finally, most of the accumulated lymphocytes die by apoptosis. The data used, thus far, to inform understanding of these processes, both in vitro and in vivo, are taken from flow cytometry experiments. One significant drawback of flow cytometry is that individual cells cannot be tracked, so that it is not possible to investigate interdependencies in the fate of cells within a family tree. This deficit in experimental information has recently been overcome by Hawkins et al. (Hawkins et al. 2009 Proc. Natl Acad. Sci. USA 106, 13 457-13 462 (doi:10.1073/pnas.0905629106)), who reported on time-lapse microscopy experiments in which B-cells were stimulated through the TLR-9 receptor. Cells stimulated in this way do not aggregate, so that data regarding family trees can be recorded. In this article, we further investigate the Hawkins et al. data. Our conclusions are striking: in order to explain the familial correlation structure in division times, death times and propensity to divide, a minimum of two distinct heritable factors are necessary. As the data show that two distinct factors are necessary, we develop a stochastic model that has two heritable factors and demonstrate that it can reproduce the key features of the data. This model shows that two heritable factors are sufficient. These deductions have a clear impact upon biological understanding of the adaptive immune response. They also necessitate changes to the fundamental premises behind the tools developed by statisticians to draw deductions from flow cytometry data. Finally, they affect the mathematical modelling paradigms that are used to study these systems, as these are widely developed based on assumptions of cellular independence that are not accurate.
authors.affiliation: Department of Electrical and Electronic Engineering, Victorian Research Laboratory, National ICT Australia, The University of Melbourne, Victoria 3010, Australia. jmarkham@wehi.edu.au
authors.forename: John F
authors.initials: JF
authors.lastname: Markham
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Wellard
authors.forename: Edwin D
authors.initials: ED
authors.lastname: Hawkins
authors.forename: Ken R
authors.initials: KR
authors.lastname: Duffy
authors.forename: Philip D
authors.initials: PD
authors.lastname: Hodgkin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002455:Cell Division; D049109:Cell Proliferation; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology