title: Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization.
abstract: It is well established how effector T cells exit the vasculature to enter the peripheral tissues in which an infection is ongoing. However, less is known regarding how CTLs migrate toward infected cells after entry into peripheral organs. Recently, it was shown that the chemokine receptor CXCR3 on T cells has an important role in their ability to localize infected cells and to control vaccinia virus infection. However, the search strategy of T cells for virus-infected targets has not been investigated in detail and could involve chemotaxis toward infected cells, chemokinesis (i.e., increased motility) combined with CTL arrest when targets are detected, or both. In this study, we describe and analyze the migration of CTLs within HSV-1-infected epidermis in vivo. We demonstrate that activated T cells display a subtle distance-dependent chemotaxis toward clusters of infected cells and confirm that this is mediated by CXCR3 and its ligands. Although the chemotactic migration is weak, computer simulations based on short-term experimental data, combined with subsequent long-term imaging indicate that this behavior is crucial for efficient target localization and T cell accumulation at effector sites. Thus, chemotactic migration of effector T cells within peripheral tissue forms an important factor in the speed with which T cells are able to arrive at sites of infection.
authors.affiliation: Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Silvia
authors.initials: S
authors.lastname: Ariotti
authors.affiliation: Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Theoretical Biology and Bioinformatics, Utrecht University, 3584 CH Utrecht, the Netherlands; Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands; and.
authors.forename: Joost B
authors.initials: JB
authors.lastname: Beltman
authors.affiliation: Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Rianne
authors.initials: R
authors.lastname: Borsje
authors.affiliation: Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Mirjam E
authors.identifier: http://orcid.org/0000-0003-4434-9813
authors.initials: ME
authors.lastname: Hoekstra
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794.
authors.forename: William P
authors.initials: WP
authors.lastname: Halford
authors.affiliation: Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: John B A G
authors.identifier: http://orcid.org/0000-0001-5884-7704
authors.initials: JB
authors.lastname: Haanen
authors.affiliation: Theoretical Biology and Bioinformatics, Utrecht University, 3584 CH Utrecht, the Netherlands;
authors.forename: Rob J
authors.identifier: http://orcid.org/0000-0002-2130-691X
authors.initials: RJ
authors.lastname: de Boer
authors.affiliation: Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; t.schumacher@nki.nl.
authors.forename: Ton N M
authors.initials: TN
authors.lastname: Schumacher
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003198:Computer Simulation; D004817:Epidermis / Q000276:immunology* / Q000821:virology; D006561:Herpes Simplex / Q000276:immunology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054367:Receptors, CXCR3 / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3