Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 21, Pages 14698-14708Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.430918
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Funding
- Tenovus Scotland grant
- Cancer Research UK
- Biotechnology and Biological Sciences Research Council
- Finnish Academy
- Arthritis Research UK
- Dundee Cancer Centre
- Medical Research Council Milstein Award
- Royal Society Industry Fellowship
- Engineering and Physical Sciences Research Council [EP/H004238/1]
- Royal Society
- EPSRC [EP/H004238/1] Funding Source: UKRI
- MRC [G0701272] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/H004238/1] Funding Source: researchfish
- Medical Research Council [G0701272] Funding Source: researchfish
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Integrins in effector T cells are highly expressed and important for trafficking of these cells and for their effector functions. However, how integrins are regulated in effector T cells remains poorly characterized. Here, we have investigated effector T cell leukocyte function-associated antigen-1 (LFA-1) regulation in primary murine effector T cells. These cells have high LFA-1 integrin expression and display high spontaneous binding to intercellular adhesion molecule-1 (ICAM-1) ligand under static conditions. In addition, these cells are able to migrate spontaneously on ICAM-1. Atomic force microscopy measurements showed that the force required for unbinding of integrin-ligand interactions increases over time (0.5-20-s contact time). The maximum unbinding force for this interaction was similar to 140 piconewtons at 0.5-s contact time, increasing to 580 piconewtons at 20-s contact time. Also, the total work required to disrupt the interaction increased over the 20-s contact time, indicating LFA-1-mediated adhesion strengthening in primary effector T cells over a very quick time frame. Effector T cells adhered spontaneously to ICAM-1 under conditions of shear flow, in the absence of chemokine stimulation, and this binding was independent of protein kinase B/Akt and protein kinase C kinase activity, but dependent on calcium/calmodulin signaling and an intact actin cytoskeleton. These results indicate that effector T cell integrins are highly expressed and spontaneously adhesive in the absence of inside-out integrin signaling but that LFA-1-mediated firm adhesion under conditions of shear flow requires downstream integrin signaling, which is dependent on calcium/calmodulin and the actin cytoskeleton.
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