Biomedical subjects

M E Binnerts

Publications and source records attributed to M E Binnerts.

5 recordsLinked to original sources

PubMed2000

Low-affinity LFA-1/ICAM-3 interactions augment LFA-1/ICAM-1-mediated T cell adhesion and signaling by redistribution of LFA-1.

Although ICAM-3 is implicated in both adhesion and signal transduction events of leukocytes, its low affinity for LFA-1 compared to other ligands of LFA-1 has puzzled many investigators. Here we investigated the role of ICAM-3 in supporting LFA-1-mediated ICAM-1 binding and subsequently cell signaling. We observed that although ICAM-3 binds poorly to LFA-1 expressed on resting T cells, it specifically facilitates and increases LFA-1-mediated adhesion to the high affinity ligand of LFA-1, ICAM-1. We demonstrate that low-affinity binding of LFA-1 to ICAM-3 together with ICAM-1 alters the cell surface distribution of LFA-1 dramatically, inducing large clusters of LFA-1 that facilitate ICAM-1 binding after LFA-1 activation. We found that LFA-1-mediated ICAM-1 cell-cell interactions such as T cell proliferation greatly depend on low affinity LFA-1/ICAM-3 interactions that enhance stable LFA-1/ICAM-1 cell-cell contact. Taken together, these data demonstrate that low affinity LFA-1 binding to ICAM-3 regulates strong LFA-1/ICAM-1-mediated adhesion by driving LFA-1 into clusters to facilitate cell-cell interactions that take place in the immune system.

Antigens, CD↗

PubMed1999

How LFA-1 binds to different ligands.

The integrin leukocyte function-associated antigen 1 (LFA-1) is pivotal for cell adhesion and signalling within the immune system. Here, Minke Binnerts and Yvette van Kooyk discuss evidence from mutational and crystallographic studies showing that binding of LFA-1 to its ligands intercellular adhesion molecule 1 (ICAM-1), -2 and -3 might be structurally distinct.

Animals↗

PubMed1996

Antibodies that selectively inhibit leukocyte function-associated antigen 1 binding to intercellular adhesion molecule-3 recognize a unique epitope within the CD11a I domain.

Several studies indicate that the I domain located in the alpha chain (CD11a) of leukocyte function-associated antigen-1 (LFA-1; CD11a/CD18) plays an essential role in ligand recognition. We recently identified three distinct epitopes (IdeA, IdeB, and IdeC) within the CD11a I domain, recognized by antibodies that block binding of LFA-1 to intercellular adhesion molecules (ICAM) 1, 2, and 3. In the present study, we used a series of human/murine CD11a I domain chimeras, to localize a fourth I domain epitope (IdeD), recognized by three independently derived anti-CD11a antibodies that selectively block the binding of LFA-1 to ICAM-3, but not to ICAM-1. The IdeD epitope depended on human CD11a residues Asp182 and Ser184 and was not present in CD11b or CD11c. Although mutation of Asp182 and Ser184 failed to abolish ICAM-3 adhesion of LFA-1 transfectants, alignment of these residues with the crystal structure of the CD11a I domain suggested that the IdeD epitope is located in close proximity to residues (Ile126 and Asn129) recently implicated in the ICAM-3 binding site. Interestingly, the IdeB and IdeC epitopes appeared to be in close proximity of a divalent cation binding pocket within the CD11a I domain that regulates both ICAM-1 and ICAM-3 adhesion. Taken together, these data indicate that distinct regions of the CD11a I domain contain epitopes for antibodies that either selectively inhibit binding of LFA-1 to ICAM-3, or interfere with both ICAM-1 and ICAM-3 binding of LFA-1.

Amino Acid Sequence↗

PubMed1996

Critical amino acids in the lymphocyte function-associated antigen-1 I domain mediate intercellular adhesion molecule 3 binding and immune function.

We have identified amino acid residues within the evolutionarily conserved I domain of the alpha-chain (CD11a) of the leukocyte integrin leukocyte function-associated antigen (LFA) 1 that are critical for intercellular adhesion molecule (ICAM) 3 (CD50) binding. ICAM-3, a ligand of LFA-1, is thought to mediate intercellular adhesion essential for the initiation of immune responses. Using a panel of human/murine I domain chimeras and point mutants, we observed that the Ile-Lys-Gly-Asn motif, located in the NH2-terminal part of the CD11a I domain, is required for ICAM-3 but not ICAM-1 binding. These findings demonstrate that the I domain of CD11a contains distinct functional subdomains for ligand specific binding. An aspartic acid located at position 137, which is essential to ICAM-1/LFA-1 interactions (Edwards, C.P., M. Champe, T. Gonzalez, M.E. Wessinger, S.A. Spencer, L.G. Presta, P.W. Berman, and S.C. Bodary. 1995. J. Biol. Chem. 270:12635-12640), was also critical for ICAM-3 binding, whereas Ser at position 139 did not effect ICAM-1 or ICAM-3 binding. A synthetic peptide containing the Ile-Lys-Gly-Asn motif inhibited ICAM-3-dependent adhesion and proliferation of T cells at micromolar concentrations, suggesting that this peptide interferes with immune recognition. These observations underscore the importance of ICAM-3 in leukocyte function, and may lead to development of a new category of immunosuppressive agents.

Amino Acid Sequence↗

PubMed1994

Distinct binding of T lymphocytes to ICAM-1, -2 or -3 upon activation of LFA-1.

LFA-1 (CD11a/CD18) mediates leukocyte adhesion by binding to one of its ligands: ICAM-1, ICAM-2 or ICAM-3. Here, we investigated whether stimuli known to induce adhesion to ICAM-1 were also capable of inducing LFA-1-mediated adhesion of T lymphocytes to ICAM-2 and -3 transfectants. We observed that phorbol 12-myristate 13-acetate, Mn2+, cross-linking of CD3 or activating antibodies against LFA-1 enhanced LFA-1-mediated T cell adhesion to ICAM-2 and -3, although to a lesser extent than to ICAM-1. These results indicate that, similar to what has been reported for adhesion to ICAM-1, activation of LFA-1 is also required for adhesion to ICAM-2 and -3. Furthermore, the results suggest that ICAM-1 is the major ligand for LFA-1 on activated T lymphocytes. Interestingly, we observed that in contrast to activating antibodies against CD18, activating antibodies against CD11a were incapable of inducing adhesion of LFA-1 to all three ligands. The antibody MEM-83 stimulated binding to ICAM-1, while at the same time inhibiting the interaction of LFA-1 with ICA8M-2 and -3. The antibody NKI-L16 selectively induced adhesion to ICAM-1 and -2, but not to ICAM-3. Our results suggest that different conformations of LFA-1 are required to support adhesion to ICAM-1, -2 or -3, and that ligands may bind on different sites of the LFA-1 molecule.

Animals↗