期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 70, 期 5, 页码 909-922出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-012-1169-0
关键词
Immune synapse; Nanobody; LFA-1; Integrin; L-plastin
资金
- Fund for Scientific Research-Flanders (FWO-Vlaanderen)
- Stichting tegen Kanker (Belgium)
- Concerted Actions Programme of Ghent University (GOA)
- Interuniversity attraction poles [IUAP06]
- Ghent University
The T cell integrin receptor LFA-1 orchestrates adhesion between T cells and antigen-presenting cells (APCs), resulting in formation of a contact zone known as the immune synapse (IS) which is supported by the cytoskeleton. L-plastin is a leukocyte-specific actin bundling protein that rapidly redistributes to the immune synapse following T cell-APC engagement. We used single domain antibodies (nanobodies, derived from camelid heavy-chain only antibodies) directed against functional and structural modules of L-plastin to investigate its contribution to formation of an immune synapse between Raji cells and human peripheral blood mononuclear cells or Jurkat T cells. Nanobodies that interact either with the EF hands or the actin binding domains of L-plastin both trapped L-plastin in an inactive conformation, causing perturbation of IS formation, MTOC docking towards the plasma membrane, T cell proliferation and IL-2 secretion. Both nanobodies delayed Ser(5) phosphorylation of L-plastin which is required for enhanced bundling activity. Moreover, one nanobody delayed LFA-1 phosphorylation, reduced the association between LFA-1 and L-plastin and prevented LFA-1 enrichment at the IS. Our findings reveal subtle mechanistic details that are difficult to attain by conventional means and show that L-plastin contributes to immune synapse formation at distinct echelons.
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