Abstract
Lymphocyte function-associated antigen 1 (LFA-1), a member of β2-integrin family, exerts multiple roles in host T cell immunity and has been identified as a useful drug-development target for inflammatory and autoimmune diseases. Applying the findings that primary resting T cells absorb nanometric membrane vesicles derived from antigen presenting cells (APC) via dual receptor/ligand interactions of T cell receptor (TCR) with cognate peptide-major histocompatibility complex (MHC) complex (pMHC) and LFA-1 with its ligand, intercellular adhesion molecule-1 (ICAM-1), and that signaling cascades triggered by TCR/pMHC interaction take a part in the vesicle-absorption, we established a cell-based high throughput assay for systematic investigation, via isolation of small molecules modulating the level of vesicle-absorption, of molecular mechanisms underlying the T cell absorption of APC-derived vesicles, i.e., structural basis of TCR/pMHC and LFA-1/ICAM-1 interactions and TCR-mediated LFA-1 activation. As primary T cells along with physiological ligands expressed in biological membrane are used and also individual cells in assay samples are analyzed by flow cytometry, results obtained using the assay system hold superior physiological and therapeutic relevance as well as statistical precision.
Highlights
Lymphocyte function-associated antigen 1 (LFA-1), an integrin composed of aL (CD11a) and b2 (CD18) subunits, plays multiple roles in T cell immunity [1]
EM pictures showed that sizes of plasma membrane-derived vesicles prepared from Dros antigen presenting cells (APC) expressing Ld plus B7-1 and intercellular adhesion molecule-1 (ICAM-1) (LdB7-1ICAM-1 Dros APCs) were relatively uniform (Supplementary Figure S1A)
Encounter of T cells with APC carrying cognate peptide-major histocompatibility complex (MHC) complex (pMHC) leads to formation of T cell receptor (TCR) microclusters followed by generation of immunological synapse (IS) at the interface of T/APC contact [31]
Summary
Lymphocyte function-associated antigen 1 (LFA-1), an integrin composed of aL (CD11a) and b2 (CD18) subunits, plays multiple roles in T cell immunity [1]. It plays a pivotal role in T cell activation by generating costimulatory signals and promoting formation of immunological synapse (IS) at the junction of T cellantigen presenting cell (APC) contact. It plays an important role in migration of effector T cells to the sites of infection and inflammation by assisting transmigration of those T cells across the vasculature. When the ‘inside-out’ signal is induced by interaction of specific receptors with their ligands, e.g., interaction of T cell receptor (TCR) with cognate peptide/MHC complexes (pMHCs), both affinity and avidity of LFA-1 for its ligand, intercellular adhesion molecule-1 (ICAM-1), are enhanced by its conformational change and spatial rearrangement
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