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In vivo TCR signaling in CD4+ T cells imprints a cell-intrinsic, transient low-motility pattern independent of chemokine receptor expression levels, or microtubular network, integrin, and protein kinase C activity

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2015
Author Ackerknecht Markus, Hauser Mark A., Legler Daniel F., Stein Jens V.,
Project Cell Migration
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Original article (peer-reviewed)

Journal Frontiers in Immunology
Volume (Issue) 6(JUN)
Page(s) 297
Title of proceedings Frontiers in Immunology
DOI 10.3389/fimmu.2015.00297

Open Access

URL http://journal.frontiersin.org/article/10.3389/fimmu.2015.00297/abstract
Type of Open Access Publisher (Gold Open Access)

Abstract

© 2015 Ackerknecht, Hauser, Legler and Stein. Intravital imaging has revealed that T cells change their migratory behavior during physiological activation inside lymphoid tissue. Yet, it remains less well investigated how the intrinsic migratory capacity of activated T cells is regulated by chemokine receptor levels or other regulatory elements. Here, we used an adjuvant-driven inflammation model to examine how motility patterns corresponded with CCR7, CXCR4, and CXCR5 expression levels on ovalbumin-specific DO11.10 CD4+ T cells in draining lymph nodes. We found that while CCR7 and CXCR4 surface levels remained essentially unaltered during the first 48-72 h after activation of CD4+ T cells, their in vitro chemokinetic and directed migratory capacity to the respective ligands, CCL19, CCL21, and CXCL12, was substantially reduced during this time window. Activated T cells recovered from this temporary decrease in motility on day 6 post immunization, coinciding with increased migration to the CXCR5 ligand CXCL13. The transiently impaired CD4+ T cell motility pattern correlated with increased LFA-1 expression and augmented phosphorylation of the microtubule regulator Stathmin on day 3 post immunization, yet neither microtubule destabilization nor integrin blocking could reverse TCR-imprinted unresponsiveness. Furthermore, protein kinase C (PKC) inhibition did not restore chemotactic activity, ruling out PKC-mediated receptor desensitization as mechanism for reduced migration in activated T cells. Thus, we identify a cell-intrinsic, chemokine receptor level-uncoupled decrease in motility in CD4+ T cells shortly after activation, coinciding with clonal expansion. The transiently reduced ability to react to chemokinetic and chemotactic stimuli may contribute to the sequestering of activated CD4+ T cells in reactive peripheral lymph nodes, allowing for integration of costimulatory signals required for full activation.
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