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The Use of Fluorescent Target Arrays for Assessment of T Cell Responses In vivo
Published on: June 19, 2014
The LFA-1-associated molecule PTA-1 (CD226) on T cells forms a dynamic molecular complex with protein 4.1G and human
Kylie J Ralston1, Samantha L Hird, Xinhai Zhang
1Cancer Research Unit, School of Biomedical Sciences, The University of Newcastle, University Drive, Callaghan, New South Wales 2308, Australia.
Insights
A newly discovered molecule, PTA-1, helps cluster T cell integrin LFA-1 at cell contact sites. This clustering is crucial for immune responses and involves dynamic protein interactions with the cytoskeleton.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- T cell integrin LFA-1 clustering at intercellular contacts is vital for immune responses.
- The mechanisms underlying LFA-1 clustering and sustained adhesion are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms responsible for clustering the T cell integrin LFA-1.
- To identify and characterize novel molecules involved in LFA-1-mediated adhesion and signaling.
Main Methods:
- Investigated the localization of LFA-1-associated molecule PTA-1 within membrane rafts.
- Examined the binding interactions between PTA-1, actin-binding protein 4.1G isoforms, and human discs large.
- Analyzed the effects of T cell stimulation on the association of PTA-1 and 4.1G with the cytoskeleton.
Main Results:
- PTA-1 localizes to membrane rafts and binds to the carboxyl-terminal domain of 4.1G isoforms.
- PTA-1's carboxyl-terminal peptide influences its binding to 4.1G and also binds human discs large.
- T cell activation leads to tight association of PTA-1 and 4.1G with the cytoskeleton, altering their binding properties.
Conclusions:
- PTA-1 plays a key role in regulating LFA-1 clustering through dynamic interactions with 4.1G and the cytoskeleton.
- These dynamic associations form a regulated molecular complex essential for clustering and transporting LFA-1 and related molecules.
- The findings provide structural insights into the molecular basis of immune cell adhesion and signaling.
Abstract:
Clustering of the T cell integrin, LFA-1, at specialized regions of intercellular contact initiates integrin-mediated adhesion and downstream signaling, events that are necessary for a successful immunological response. But how clustering is achieved and sustained is not known. Here we establish that an LFA-1-associated molecule, PTA-1, is localized to membrane rafts and binds the carboxyl-terminal domain of isoforms of the actin-binding protein 4.1G. Protein 4.1 is known to associate with the membrane-associated guanylate kinase homologue, human discs large. We show that the carboxyl-terminal peptide of PTA-1 also can bind human discs large and that the presence or absence of this peptide greatly influences binding between PTA-1 and different isoforms of 4.1G. T cell stimulation with phorbol ester or PTA-1 cross-linking induces PTA-1 and 4.1G to associate tightly with the cytoskeleton, and the PTA-1 from such activated cells now can bind to the amino-terminal region of 4.1G. We propose that these dynamic associations provide the structural basis for a regulated molecular adhesive complex that serves to cluster and transport LFA-1 and associated molecules.
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