title: Predicting pathogen-specific CD8 T cell immune responses from a modeling approach.
abstract: The primary CD8 T cell immune response constitutes a major mechanism to fight an infection by intra-cellular pathogens. We aim at assessing whether pathogen-specific dynamical parameters of the CD8 T cell response can be identified, based on measurements of CD8 T cell counts, using a modeling approach. We generated experimental data consisting in CD8 T cell counts kinetics during the response to three different live intra-cellular pathogens: two viruses (influenza, vaccinia) injected intranasally, and one bacteria (Listeria monocytogenes) injected intravenously. All pathogens harbor the same antigen (NP68), but differ in their interaction with the host. In parallel, we developed a mathematical model describing the evolution of CD8 T cell counts and pathogen amount during an immune response. This model is characterized by 9 parameters and includes relevant feedback controls. The model outputs were compared with the three data series and an exhaustive estimation of the parameter values was performed. By focusing on the ability of the model to fit experimental data and to produce a CD8 T cell population mainly composed of memory cells at the end of the response, critical parameters were identified. We show that a small number of parameters (2-4) define the main features of the CD8 T cell immune response and are characteristic of a given pathogen. Among these parameters, two are related to the effector CD8 T cell mediated control of cell and pathogen death. The parameter associated with memory cell death is shown to play no relevant role during the main phases of the CD8 T cell response, yet it becomes essential when looking at the predictions of the model several months after the infection.
authors.affiliation: Université de Lyon, Université Lyon 1, CNRS UMR 5208, Institut Camille Jordan 43 blvd du 11 novembre 1918, F-69622 Villeurbanne-Cedex, France; Inria Team Dracula, Inria Center Grenoble Rhône-Alpes, France. Electronic address: crauste@math.univ-lyon1.fr.
authors.forename: F
authors.initials: F
authors.lastname: Crauste
authors.affiliation: Université de Lyon, Université Lyon 1, CNRS UMR 5208, Institut Camille Jordan 43 blvd du 11 novembre 1918, F-69622 Villeurbanne-Cedex, France; Inria Team Dracula, Inria Center Grenoble Rhône-Alpes, France; Université de Lyon, Université Lyon 1, CNRS UMR 5534, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, F-69622 Villeurbanne-Cedex, France. Electronic address: emterry@free.fr.
authors.forename: E
authors.initials: E
authors.lastname: Terry
authors.affiliation: CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France. Electronic address: isabelle.lemercier@Dartmouth.edu.
authors.forename: I Le
authors.initials: IL
authors.lastname: Mercier
authors.affiliation: CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France. Electronic address: julien.mafille@inserm.fr.
authors.forename: J
authors.initials: J
authors.lastname: Mafille
authors.affiliation: CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France. Electronic address: sophia.djebali@inserm.fr.
authors.forename: S
authors.initials: S
authors.lastname: Djebali
authors.affiliation: CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France. Electronic address: thibault.andrieu@inserm.fr.
authors.forename: T
authors.initials: T
authors.lastname: Andrieu
authors.affiliation: CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France. Electronic address: blandine.mercier@inserm.fr.
authors.forename: B
authors.initials: B
authors.lastname: Mercier
authors.affiliation: Université de Lyon, Université Lyon 1, CNRS UMR 5534, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, F-69622 Villeurbanne-Cedex, France; Université de Lyon, INSA-Lyon, INRIA, Laboratoire d׳InfoRmatique en Image et Systèmes d׳information (LIRIS), CNRS UMR5205, F-69621 Lyon, France. Electronic address: gael.kaneko@gmail.com.
authors.forename: G
authors.initials: G
authors.lastname: Kaneko
authors.affiliation: CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France. Electronic address: christophe.arpin@inserm.fr.
authors.forename: C
authors.initials: C
authors.lastname: Arpin
authors.affiliation: CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France.
authors.forename: J
authors.initials: J
authors.lastname: Marvel
authors.affiliation: Inria Team Dracula, Inria Center Grenoble Rhône-Alpes, France; Université de Lyon, Université Lyon 1, CNRS UMR 5534, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, F-69622 Villeurbanne-Cedex, France. Electronic address: Olivier.Gandrillon@univ-lyon1.fr.
authors.forename: O
authors.initials: O
authors.lastname: Gandrillon
mesh_terms: D000465:Algorithms; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D006801:Humans; D007156:Immunologic Memory; D007251:Influenza, Human / Q000276:immunology*; D008089:Listeria monocytogenes; D008088:Listeriosis / Q000276:immunology*; D018655:Lymphocyte Count; D051379:Mice; D008954:Models, Biological; D009975:Orthomyxoviridae; D009976:Orthomyxoviridae Infections / Q000276:immunology; D015203:Reproducibility of Results; D014615:Vaccinia / Q000276:immunology*; D014616:Vaccinia virus
keywords: CD8 T cells; Immune response; Nonlinear model; Parameter value estimation; Predictive model