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J Immunol ; 195(11): 5285-95, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26525288


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.

Quimiotaxia de Leucócito/imunologia , Epiderme/imunologia , Herpes Simples/imunologia , Receptores CXCR3/imunologia , Linfócitos T Citotóxicos/imunologia , Transferência Adotiva , Animais , Simulação por Computador , Epiderme/virologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
Trends Immunol ; 36(7): 392-400, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26072285


Upon infection, antigen-specific T lymphocytes become activated, proliferate, differentiate, and acquire various effector functions. Much of our understanding of the molecular mechanisms underlying these processes derives from studies leveraging gene deletion, RNAi, and overexpression approaches. However, these perturbations do not inform on the regulation of gene activity under physiological conditions. Genetic reporter systems that couple biological events to detectable output signals are capable of providing this information. Here, we review the reporter approaches being currently used to investigate various aspects of T cell behavior, and discuss advantages and disadvantages inherent to different designs. We outline emerging applications based on recent advances in other fields, and highlight the potential of synthetic biology and genome engineering to address open questions in the field.

Diferenciação Celular/genética , Genes Reporter/genética , Engenharia Genética , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Humanos , Linfócitos T/metabolismo
Science ; 346(6205): 101-5, 2014 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-25278612


After an infection, pathogen-specific tissue-resident memory T cells (T(RM) cells) persist in nonlymphoid tissues to provide rapid control upon reinfection, and vaccination strategies that create T(RM) cell pools at sites of pathogen entry are therefore attractive. However, it is not well understood how T(RM) cells provide such pathogen protection. Here, we demonstrate that activated T(RM) cells in mouse skin profoundly alter the local tissue environment by inducing a number of broadly active antiviral and antibacterial genes. This "pathogen alert" allows skin T(RM) cells to protect against an antigenically unrelated virus. These data describe a mechanism by which tissue-resident memory CD8(+) T cells protect previously infected sites that is rapid, amplifies the activation of a small number of cells into an organ-wide response, and has the capacity to control escape variants.

Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Pele/imunologia , Animais , Feminino , Memória Imunológica/genética , Masculino , Camundongos , Pele/microbiologia , Pele/virologia , Transcriptoma
J Biol Chem ; 289(1): 520-8, 2014 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-24235148


Mouse dendritic cells (DCs) can rapidly extend their Class II MHC-positive late endosomal compartments into tubular structures, induced by Toll-like receptor (TLR) triggering. Within antigen-presenting DCs, tubular endosomes polarize toward antigen-specific CD4(+) T cells, which are considered beneficial for their activation. Here we describe that also in human DCs, TLR triggering induces tubular late endosomes, labeled by fluorescent LDL. TLR triggering was insufficient for induced tubulation of transferrin-positive endosomal recycling compartments (ERCs) in human monocyte-derived DCs. We studied endosomal remodeling in human DCs in co-cultures of DCs with CD8(+) T cells. Tubulation of ERCs within human DCs requires antigen-specific CD8(+) T cell interaction. Tubular remodeling of endosomes occurs within 30 min of T cell contact and involves ligation of HLA-A2 and ICAM-1 by T cell-expressed T cell receptor and LFA-1, respectively. Disintegration of microtubules or inhibition of endosomal recycling abolished tubular ERCs, which coincided with reduced antigen-dependent CD8(+) T cell activation. Based on these data, we propose that remodeling of transferrin-positive ERCs in human DCs involves both innate and T cell-derived signals.

Apresentação do Antígeno/fisiologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Endossomos/imunologia , Monócitos/imunologia , Receptores Toll-Like/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/citologia , Feminino , Antígeno HLA-A2/imunologia , Humanos , Imunidade Celular/fisiologia , Imunidade Inata/fisiologia , Molécula 1 de Adesão Intercelular/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Masculino , Camundongos , Monócitos/citologia , Transdução de Sinais/fisiologia
Proc Natl Acad Sci U S A ; 109(48): 19739-44, 2012 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-23150545


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.

Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Epitélio/imunologia , Humanos