TY - JOUR
T1 - Cyton2
T2 - A Model of Immune Cell Population Dynamics That Includes Familial Instructional Inheritance
AU - Cheon, HoChan
AU - Kan, Andrey
AU - Prevedello, Giulio
AU - Oostindie, Simone C.
AU - Dovedi, Simon J.
AU - Hawkins, Edwin D.
AU - Marchingo, Julia M.
AU - Heinzel, Susanne
AU - Duffy, Ken R.
AU - Hodgkin, Philip D.
N1 - Funding Information:
This project has received funding from the European Union’s Horizon 2020 research and innovation programmed under the Marie Marie Skłodowska-Curie grant agreement No 764698. This publication has emanated from research supported in part by a research grant from Science Foundation Ireland (SFI) under Grant Number 16/RI/3399. This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (Project Grant 1164800 and Investigator Grant 1176588 to P.D.H.), Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC Independent Research Institutes Infrastructure Support Scheme (361646). J.M.M is supported by an NHMRC CJ Martin Fellowship. E.D.H is supported by NHMRC R.D. Wright Fellowship and project grants (1159488, 1140187, and 1165591) and grants from The Leukemia and Lymphoma Society (6552-18).
Copyright:
© 2021 Cheon, Kan, Prevedello, Oostindie, Dovedi, Hawkins, Marchingo, Heinzel, Duffy and Hodgkin.
PY - 2021/10/28
Y1 - 2021/10/28
N2 - Lymphocytes are the central actors in adaptive immune responses. When challenged with antigen, a small number of B and T cells have a cognate receptor capable of recognising and responding to the insult. These cells proliferate, building an exponentially growing, differentiating clone army to fight off the threat, before ceasing to divide and dying over a period of weeks, leaving in their wake memory cells that are primed to rapidly respond to any repeated infection. Due to the non-linearity of lymphocyte population dynamics, mathematical models are needed to interrogate data from experimental studies. Due to lack of evidence to the contrary and appealing to arguments based on Occam's Razor, in these models newly born progeny are typically assumed to behave independently of their predecessors. Recent experimental studies, however, challenge that assumption, making clear that there is substantial inheritance of timed fate changes from each cell by its offspring, calling for a revision to the existing mathematical modelling paradigms used for information extraction. By assessing long-term live-cell imaging of stimulated murine B and T cells in vitro, we distilled the key phenomena of these within-family inheritances and used them to develop a new mathematical model, Cyton2, that encapsulates them. We establish the model's consistency with these newly observed fine-grained features. Two natural concerns for any model that includes familial correlations would be that it is overparameterised or computationally inefficient in data fitting, but neither is the case for Cyton2. We demonstrate Cyton2's utility by challenging it with high-throughput flow cytometry data, which confirms the robustness of its parameter estimation as well as its ability to extract biological meaning from complex mixed stimulation experiments. Cyton2, therefore, offers an alternate mathematical model, one that is, more aligned to experimental observation, for drawing inferences on lymphocyte population dynamics.
AB - Lymphocytes are the central actors in adaptive immune responses. When challenged with antigen, a small number of B and T cells have a cognate receptor capable of recognising and responding to the insult. These cells proliferate, building an exponentially growing, differentiating clone army to fight off the threat, before ceasing to divide and dying over a period of weeks, leaving in their wake memory cells that are primed to rapidly respond to any repeated infection. Due to the non-linearity of lymphocyte population dynamics, mathematical models are needed to interrogate data from experimental studies. Due to lack of evidence to the contrary and appealing to arguments based on Occam's Razor, in these models newly born progeny are typically assumed to behave independently of their predecessors. Recent experimental studies, however, challenge that assumption, making clear that there is substantial inheritance of timed fate changes from each cell by its offspring, calling for a revision to the existing mathematical modelling paradigms used for information extraction. By assessing long-term live-cell imaging of stimulated murine B and T cells in vitro, we distilled the key phenomena of these within-family inheritances and used them to develop a new mathematical model, Cyton2, that encapsulates them. We establish the model's consistency with these newly observed fine-grained features. Two natural concerns for any model that includes familial correlations would be that it is overparameterised or computationally inefficient in data fitting, but neither is the case for Cyton2. We demonstrate Cyton2's utility by challenging it with high-throughput flow cytometry data, which confirms the robustness of its parameter estimation as well as its ability to extract biological meaning from complex mixed stimulation experiments. Cyton2, therefore, offers an alternate mathematical model, one that is, more aligned to experimental observation, for drawing inferences on lymphocyte population dynamics.
KW - immune response
KW - population dynamics
KW - mathematical model
KW - familial correlations
KW - proliferation
U2 - 10.3389/fbinf.2021.723337
DO - 10.3389/fbinf.2021.723337
M3 - Article
C2 - 36303793
SN - 2673-7647
VL - 1
JO - Frontiers in Bioinformatics
JF - Frontiers in Bioinformatics
M1 - 723337
ER -