Mac-1 (CD11b/CD18) is essential for Fc receptor–mediated neutrophil cytotoxicity and immunologic synapse formation

Abstract

IntroductionAntibodies have been studied extensively for their use in immunotherapy of cancer. [1][2][3][4] It is evident that receptors for the Fc portion of immunoglobulins (FcRs) on myeloid cells are critical in triggering antitumor cytotoxicity in vivo. 5,6 Antibody-dependent cellular cytotoxicity (ADCC), considered crucial for antibody-mediated tumor cell degradation, can be mediated by polymorphonuclear leukocytes (PMNs), monocytes/macrophages, eosinophils, and natural killer (NK) cells. 7,8 These effector cells use different cytotoxic mechanisms, depending on their activation state and the nature of the target. 7,9-12 PMNs, representing the most populous type of white blood cell, exhibit fast recruitment activity in vivo. Potent and very rapid (within 30 minutes) PMN cytotoxicity toward various tumor targets has been documented. 10,[13][14][15] Two classes of immunoglobulin (Ig)G receptors (Fc␥RIIa, CD32, and Fc␥RIIIb, CD16) and one class of IgA receptor (Fc␣RI, CD89) have been identified on human PMNs, whereas Fc␥RI (CD64) expression is inducible on PMNs on stimulation with granulocyte colony-stimulating factor. 16 PMNs can trigger ADCC by engagement of Fc␥RI, Fc␥RIIa, and Fc␣RI. Fc␣RI, however, has been observed to be the most effective FcR for PMN-mediated tumor cell killing. 14,17 Mac-1 (CR3, CD11b/CD18) is a member of the ␤ 2 integrin family, which includes Mac-1, LFA-1 (CD11a/CD18), and gp150/95 (CR4, CD11c/CD18). 18,19 These receptors, sharing a common ␤-chain (CD18), can bind multiple ligands and can regulate various leukocyte functions. Mac-1 represents the predominant ␤ 2 integrin on PMNs and is furthermore expressed on monocytes/macrophages and NK cells. Several PMN functions are regulated by Mac-1, including adhesion, migration, chemotaxis, phagocytosis, respiratory burst activity, and degranulation. 18 On activation, Mac-1 is able to initiate signaling by its linkage to the actin cytoskeleton and associated signaling proteins. 20,21 A number of studies described Mac-1 cooperation with different receptors on PMNs, indicating Mac-1 to be a signaling partner for other receptors. 22 These include FMLP receptors, LPS/LBP receptors (CD14), urokinase plasminogen activator receptor (CD87), and Fc receptors. [22][23][24][25][26] Mac-1 was found to trigger Ab-dependent phagocytosis by Fc␥RIIIb in fibroblasts transfected with both Mac-1 and Fc␥RIIIb, whereas cells expressing only Mac-1 or Fc␥RIIIb were unable to ingest Ab-opsonized particles. 27 Mac-1 cooperation with Fc␥RIIIb in the generation of PMN respiratory burst has been described as well. 28 Furthermore, Mac-1 restored IgG-dependent phagocytosis of transfectants with Fc␥RIIa tail-minus mutants. 29 Importantly, PMNs from patients with leukocyte adhesion deficiency, who lack CD18, were shown to be severely impaired in mediating phagocytosis and ADCC. 18,[30][31][32] Although the relative contribution of individual ␤ 2 integrins remains to be determined, various studies point to an important role of Mac-1 in FcR-mediated cytotoxicity. Targets st...

Regulation of dextran sodium sulfate induced colitis by leukocyte beta 2 integrins

“…49,52 Therefore, it is surprising that CD11b null mice display enhanced DSS colitis. A previous report by Coxon et al 53 has shown that CD11b plays a role in regulating neutrophil apoptosis such that genetic loss of CD11b delays apoptosis thereby possibly increasing the capacity for tissue damage.…”

The Calcineurin B Subunit (CnB) Is a New Ligand of Integrin αM That Mediates CnB-Induced Apo2L/TRAIL Expression in Macrophages

“…Several groups have reported that tumor-infiltrating integrin aM-positive cells support tumor growth by, for example, stimulating angiogenesis and neovascularization (50)(51)(52). In contrast, integrin aMb 2 is crucial for effective FcR-mediated immunity to melanoma (53) and promotes the survival of mouse NK cells (54). In addition, it inhibits TLR-triggered inflammatory responses and prevents excessive production of proinflammatory cytokines and type I IFN (55).…”

A Recombinant Bispecific Single-Chain Fragment Variable Specific for HLA Class II and FcαRI (CD89) Recruits Polymorphonuclear Neutrophils for Efficient Lysis of Malignant B Lymphoid Cells

“…These data reflect the different demands of individual effector populations for effective target cell killing. Consequently, for PMNs the nature of the target Ag or associated surface molecules (adhesion molecules) might represent the outstanding parameters (35).…”