Ligands

Three ICAMs

The only ligands identified for LFA-1 (other than microbial ligands, see below) are the intercellular adhesion molecules ICAM-1 (CD54), ICAM-2 (CD102), and ICAM-3 (CD50), all of which bind in a temperature- and magnesium-dependent manner. Antibody blocking experiments are consistent with these being all of LFA-l's ligands. The three ICAMs are each glycosylated integral membrane proteins with a single transmembrane domain, and extracellular domains consisting of tandem head-to-tail immunoglobulin superfamily domains (Figure 1). All have rod-like configurations (ICAM-1 being bent), and in each case, one or two N-terminal domains

(farthest from the membrane) contains the LFA-I-binding site. ICAM-3, at least, can generate cytoplasmic signals, since certain antibodies to ICAM-3 activate LFA-1, VLA-4 and VLA-5.

ICAM-1 and ICAM-3 are heavily glycosylated (90-124 kDa, 55-59 kDa core proteins). ICAM-2 may be as well since it contains six predicted N-linked glycosylation sites. Different cell types glycosylate ICAMs differently. This affects binding of ICAM-1 to CD1 lb/CDl 8, but all forms of ICAM-3 appear to bind equally well to CDlla/CD18. CD lib/CD 18 binds ICAM-1, but neither CDllb/ CD18 nor CDllc/CD18 bind ICAM-3.

ICAM expression

ICAM-1 is expressed in most tissues at low levels, and expression is readily increased by inflammatory-cytokines. In contrast, ICAM-2 is expressed primarily on endothelium and leukocytes (except neutrophils), and its expression generally is not responsive to cytokines. ICAM-3 is expressed on leukocytes and Langerhans cells, but not resting nor cytokine-induced endothelium, nor nonhemato-poietic tissues. ICAM-3 predominates on thymocytes and resting lymphocytes, which are low in ICAM-1. When neutrophils are activated, they shed the majority of their ICAM-3 into the medium by proteolytic cleavage.

Microbial ligands

CD18 binds to certain bacteria (Escherichia coli) and fungi (Histoplasma capsulatum) in a temperature-and divalent cation-dependent manner. This is crucial for phagocytosis of the unopsonized forms of these microbes. Rhinovirus binds to ICAM-1 in a divalent cation-independent manner. Plasmodium falciparum also binds to ICAM-1, and both microbes depend on this binding for successful infection.

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