Abstract
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.
Highlights
Naive lymphocytes continuously home via high endothelial venules (HEVs) to secondary lymphoid organs including peripheral lymph nodes (PLNs) in search of cognate Ag [1,2,3]
Kinetic Analysis of Expansion and Activation Marker Expression of OVA-Specific DO11.10 CD4+ T Cells During Inflammation Previous 2PM studies of reactive PLNs have shown that DO11.10 CD4+ T cells decreased their migration speed after activation by DCs, often moving slowly in spatially confined “swarms” [4, 6]
To mimic experimental conditions used in previous 2PM studies, we transferred 2 to 3 × 106 DO11.10 CD4+ T cells into syngeneic Balb/c recipient mice, which were s.c. immunized 1 day later with OVA emulsified in complete Freund’s adjuvant (CFA)
Summary
Naive lymphocytes continuously home via high endothelial venules (HEVs) to secondary lymphoid organs including peripheral lymph nodes (PLNs) in search of cognate Ag [1,2,3]. TCR-controlled T cell motility live two-photon microscopy (2PM) imaging has uncovered that in non-reactive PLNs, naïve T cells perform random guided walk on stromal cells of the T cell area with an average speed of 10–15 μm/min [4,5,6,7,8,9]. In the days following primary DC imprinting, CD4+ T cells remain capable to integrate secondary signals derived from late-arriving DC immigrants [10]. This is in line with the observation that long-dwell times in lymphoid tissue presenting cognate pMHC complexes is required for full CD4+ T cell activation [11]
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