Abstract
ABSTRACTAntigen-specific adhesion between T cells and antigen-presenting cells (APC) during the formation of the immunological synapse (IS) is mediated by LFA-1 and ICAM-1. Here, LFA-1–ICAM-1 interactions were measured at the single-molecule level on supported lipid bilayers. High-affinity binding was detected at low frequencies in the inner peripheral supramolecular activation cluster (SMAC) zone that contained high levels of activated Rap1 and kindlin-3. Rap1 was essential for T cell attachment, whereas deficiencies of ste20-like kinases, Mst1/Mst2, diminished high-affinity binding and abrogated central SMAC (cSMAC) formation with mislocalized kindlin-3 and vesicle transport regulators involved in T cell receptor recycling/releasing machineries, resulting in impaired T cell-APC interactions. We found that NDR1 kinase, activated by the Rap1 signaling cascade through RAPL and Mst1/Mst2, associated with and recruited kindlin-3 to the IS, which was required for high-affinity LFA-1/ICAM-1 binding and cSMAC formation. Our findings reveal crucial roles for Rap1 signaling via NDR1 for recruitment of kindlin-3 and IS organization.
Highlights
Antigen-specific adhesion between T cells and antigen-presenting cells (APC) during the formation of the immunological synapse (IS) is mediated by LFA-1 and ICAM-1
We found that NDR1 kinase, activated by the Rap1 signaling cascade through RAPL and Mst1/Mst2, associated with and recruited kindlin-3 to the IS, which was required for high-affinity LFA-1/ICAM-1 binding and central SMAC (cSMAC) formation
Antigen-specific T cell and antigenpresenting cell (T-APC) interactions have been extensively studied in the immunological synapse (IS), which is composed of a central supramolecular activation cluster of T cell receptor (TCR)-peptide major histocompatibility complex surrounded by a peripheral ring of LFA-1/ICAM-1 and associated talin and a distal supramolecular activation cluster of F-actin [4,5,6]
Summary
Antigen-specific adhesion between T cells and antigen-presenting cells (APC) during the formation of the immunological synapse (IS) is mediated by LFA-1 and ICAM-1. It is generally thought that inside-out signals cause direct binding of talin-1 and kindlin-3 to the tail region of the  subunits, leading to a separation of ␣/ integrin cytoplasmic tails, which induces conformational changes to the stalk and headpiece regions, resulting in a shift from bent low-affinity to extended intermediate- and high-affinity conformations [16, 20, 24, 25]. It is still unclear how heterogeneous binding events of LFA-1 and ICAM-1 are regulated by inside-out signals and IS formation through talin and kindlin-3
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