title: How is the effectiveness of immune surveillance impacted by the spatial distribution of spreading infections?
abstract: What effect does the spatial distribution of infected cells have on the efficiency of their removal by immune cells, such as cytotoxic T lymphocytes (CTL)? If infected cells spread in clusters, CTL may initially be slow to locate them but subsequently kill more rapidly than in diffuse infections. We address this question using stochastic, spatially explicit models of CTL interacting with different patterns of infection. Rather than the effector : target ratio, we show that the relevant quantity is the ratio of a CTL's expected time to locate its next target (search time) to the average time it spends conjugated with a target that it is killing (handling time). For inefficient (slow) CTL, when the search time is always limiting, the critical density of CTL (that required to control 50% of infections, C(*)) is independent of the spatial distribution and derives from simple mass-action kinetics. For more efficient CTL such that handling time becomes limiting, mass-action underestimates C(*), and the more clustered an infection the greater is C(*). If CTL migrate chemotactically towards targets the converse holds-C(*) falls, and clustered infections are controlled most efficiently. Real infections are likely to spread patchily; this combined with even weak chemotaxis means that sterilizing immunity may be achieved with substantially lower numbers of CTL than standard models predict.
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Ulrich D
authors.initials: UD
authors.lastname: Kadolsky
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK andrew.yates@glasgow.ac.uk.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Yates
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte; D003198:Computer Simulation; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007157:Immunologic Surveillance; D007239:Infections / Q000276:immunology*; D018448:Models, Immunological; D013269:Stochastic Processes; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
keywords: computational immunology; cytotoxic T cells; spatial modelling