Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen

Recent work has demonstrated that following the clearance of infection a stable population of memory T cells remains present in peripheral organs and contributes to the control of secondary infections. However, little is known about how tissue-resident memory T cells behave in situ and how they encounter newly infected target cells. Here we demonstrate that antigen-specific CD8+ T cells that remain in skin following herpes simplex virus infection show a steady-state crawling behavior in between keratinocytes. Spatially explicit simulations of the migration of these tissue-resident memory T cells indicate that the migratory dendritic behavior of these cells allows the detection of antigen-expressing target cells in physiologically relevant time frames of minutes to hours. Furthermore, we provide direct evidence for the identification of rare antigen-expressing epithelial cells by skin-patrolling memory T cells in vivo. These data demonstrate the existence of skin patrol by memory T cells and reveal the value of this patrol in the rapid detection of renewed infections at a previously infected site.

[1]  M. Bevan,et al.  Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence , 2010, Proceedings of the National Academy of Sciences.

[2]  P. Bousso,et al.  CD4+ T cells rely on a cytokine gradient to control intracellular pathogens beyond sites of antigen presentation. , 2012, Immunity.

[3]  M. Bevan.  Memory T cells as an occupying force , 2011, European journal of immunology.

[4]  Atsushi Miyawaki,et al.  Monitoring cellular movement in vivo with photoconvertible fluorescence protein “Kaede” transgenic mice , 2008, Proceedings of the National Academy of Sciences.

[5]  R. Clark,et al.  Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity , 2012, Nature.

[6]  W. J. Mulholland,et al.  Multiphoton high-resolution 3D imaging of Langerhans cells and keratinocytes in the mouse skin model adopted for epidermal powdered immunization. , 2006, The Journal of investigative dermatology.

[7]  Scott N. Mueller,et al.  Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation , 2012, Proceedings of the National Academy of Sciences.

[8]  Mark J. Miller,et al.  Two-Photon Imaging of Lymphocyte Motility and Antigen Response in Intact Lymph Node , 2002, Science.

[9]  R. Diefenbach,et al.  Transport and egress of herpes simplex virus in neurons , 2008, Reviews in medical virology.

[10]  Andrea J. Liu,et al.  Generalized Lévy walks and the role of chemokines in migration of effector CD8+ T cells , 2012, Nature.

[11]  R. Webby,et al.  Dynamic T cell migration program provides resident memory within intestinal epithelium , 2010, The Journal of experimental medicine.

[12]  F. Carbone,et al.  Characterization of diverse primary herpes simplex virus type 1 gB-specific cytotoxic T-cell response showing a preferential V beta bias , 1995, Journal of virology.

[13]  Glazier,et al.  Simulation of the differential adhesion driven rearrangement of biological cells. , 1993, Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics.

[14]  Joost B. Beltman,et al.  Lymph node topology dictates T cell migration behavior , 2007, The Journal of experimental medicine.

[15]  Glazier,et al.  Simulation of biological cell sorting using a two-dimensional extended Potts model. , 1992, Physical review letters.

[16]  H. Ploegh,et al.  Behavioral responses of epidermal Langerhans cells in situ to local pathological stimuli. , 2006, The Journal of investigative dermatology.

[17]  P. Doherty,et al.  Cutting Edge: Tissue-Resident Memory CTL Down-Regulate Cytolytic Molecule Expression following Virus Clearance1 , 2007, The Journal of Immunology.

[18]  Thomas Gebhardt,et al.  Different patterns of peripheral migration by memory CD4+ and CD8+ T cells , 2011, Nature.

[19]  M. Amagai,et al.  External antigen uptake by Langerhans cells with reorganization of epidermal tight junction barriers , 2009, The Journal of experimental medicine.

[20]  S. Henrickson,et al.  T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases , 2004, Nature.

[21]  T. Schumacher,et al.  Behavior and function of tissue-resident memory T cells. , 2012, Advances in immunology.

[22]  T. Zal,et al.  Body barrier surveillance by epidermal gammadelta TCR , 2012, Nature Immunology.

[23]  Chien-Fu Hung,et al.  A rapid and potent DNA vaccination strategy defined by in vivo monitoring of antigen expression , 2005, Nature Medicine.

[24]  Thomas Gebhardt,et al.  Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus , 2009, Nature Immunology.

[25]  A. F. Marée,et al.  Spatial modelling of brief and long interactions between T cells and dendritic cells , 2007, Immunology and cell biology.