Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 37, Issue 8, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00424-16
Keywords
ICAM-1; immunological synapse; LFA-1; NDR1; Rap1; single-molecule measurement; vesicular transport
Categories
Funding
- CREST
- Japan Science Technology Agency
- KAKENHI from the Ministry of Education, Science, Sport and Culture of Japan
- [15K21524]
- [22111003]
- [25291047]
- Grants-in-Aid for Scientific Research [17K18253, 15K21524] Funding Source: KAKEN
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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. 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 mis-localized 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.
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