Regulated Ca2+ signalling through leukocyte CD11b/CD18 integrin.
General mechanisms of adhesion in the immune response are coordinated by the leukocyte integrins CD11/CD18. The possible participation of these differentiation molecules in early events of transmembrane signalling was investigated. Monoclonal antibody (mAb) cross-linking of CD18, the integrin beta subunit ubiquitously expressed by all leukocytes, increased the cytosolic free Ca2+ concentration ([Ca2+]i) by 2-3-fold in monocyte THP-1 cells. Digitalized imaging in single adherent cells showed that this Ca2+ response is temporally biphasic, involves both release of Ca2+ from the intracellular stores as well as Ca2+ influx from the external compartment, and is dramatically down-modulated by terminal differentiation of THP-1 cells to a mature monocyte phenotype. Similarly, only a minor subset of 20-30% of peripheral blood monocytes heterogeneously maintain the CD18-mediated Ca(2+)-signalling properties. Cross-linking of CD18 also increased cytosolic free [Ca2+]i in a subset of approx. 15-20% of resting T lymphocytes, in a Ca2+ response that was completely abrogated during T-cell mitogenic activation with lectins or alloreactive antigen. While cross-linking of CD11a or CD11c was without effect, occupancy of CD11b increased cytosolic free [Ca2+]i in monocytic cells. This response was functionally coupled with a transient activation state of CD11b/CD18, which was reflected in its increased avidity to bind the complementary ligand fibrinogen. These results suggest that occupancy of CD18 transduces a stimulatory Ca2+ signal that is critically regulated by the state of cell activation/differentiation and by the association with the unique alpha-subunit CD11b. These intrinsic signalling properties may directly participate in regulating the oligospecific ligand recognition of leukocyte integrins.
Department of Immunology, Scripps Research Institute, La Jolla, CA 92037.
D C
DC
Altieri
S J
SJ
Stamnes
C G
CG
Gahmberg
D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000502:physiology*; D018845:CD11 Antigens; D018821:CD18 Antigens; D002118:Calcium / Q000502:physiology*; D002454:Cell Differentiation; D003600:Cytosol / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008213:Lymphocyte Activation; D009000:Monocytes / Q000502:physiology; D011940:Receptor Aggregation; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018845:CD11 Antigens; D018821:CD18 Antigens; D008024:Ligands; D005340:Fibrinogen; D002118:Calcium