Phagocytosis of Mycobacterium leprae by human monocyte-derived macrophages is mediated by complement receptors CR1 (CD35), CR3 (CD11b/CD18), and CR4 (CD11c/CD18) and IFN-gamma activation inhibits complement receptor function and phagocytosis of this bacterium.
We have examined phagocytosis of Mycobacterium leprae by human monocyte-derived macrophages (MDM). Compared with monocytes, MDM exhibit greatly enhanced adherence of M. leprae (6.5 +/- 2-fold increase). MDM adherence of M. leprae is serum dependent and requires heat-labile serum components because heat inactivation of serum reduces adherence by 70 +/- 3%. mAb against C receptors CR1 (CD35), CR3 (CD11b/CD18), and CR4 (CD11c/CD18) inhibit phagocytosis of M. leprae in fresh nonimmune serum. Single mAb against each receptor inhibit M. leprae adherence by 25 +/- 4% - 33 +/- 6%. Single mAb used in combination against all three receptors inhibit M. leprae adherence by 51 +/- 6%. Most significantly, pairs of mAb used in combination against all three receptors inhibit by 80 +/- 4%. By electron microscopy, MDM ingest all M. leprae that adhere in fresh nonimmune serum. In the presence of mAb against CR1, CR3, and CR4, the percentage of MDM cross-sections that contain intracellular bacteria is reduced 66 +/- 3% and the mean number of bacteria per cross-section is reduced 78 +/- 10%. MDM activated by IFN-gamma exhibit markedly reduced adherence (by light microscopy) and ingestion (by electron microscopy) of M. leprae. MDM in culture for 5 days inhibit M. leprae adherence by 83 +/- 2% and ingestion by 88% when activated for 5 days. Paralleling this, IFN-gamma-activated MDM exhibit markedly reduced C receptor function, reflected by markedly decreased adherence and ingestion of C3b- and C3bi-coated E. Decreased C receptor function by IFN-gamma-activated MDM correlates with decreased surface expression of CR1 but not CR3 or CR4. CR1 expression on MDM in culture for 5 days is reduced by 32 +/- 9% and 75 +/- 3% after IFN-gamma activation for 5 and 2 days, respectively. This study demonstrates that MDM have an enhanced capacity to phagocytize M. leprae, and that in addition to CR1 and CR3, phagocytosis involves CR4, whose expression on MDM is highly maturation-dependent. This study also demonstrates that IFN-gamma activation markedly reduces the capacity of MDM to phagocytize M. leprae, and it provides a molecular mechanism for this phenomenon-decreased C receptor function.
Schlesinger
L S
LS
Department of Medicine, UCLA School of Medicine 90024-1688.
Horwitz
M A
MA
D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000502:physiology*; D001770:Blood Bactericidal Activity; D018845:CD11 Antigens; D018821:CD18 Antigens; D002448:Cell Adhesion; D015536:Down-Regulation; D005353:Fibronectins / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D037181:Lectins, C-Type; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000276:immunology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009000:Monocytes / Q000166:cytology; D009166:Mycobacterium leprae / Q000276:immunology*; D010587:Phagocytosis; D011956:Receptors, Cell Surface; D011951:Receptors, Complement / Q000502:physiology*; D017463:Receptors, Complement 3b; D011971:Receptors, Immunologic / Q000502:physiology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018845:CD11 Antigens; D018821:CD18 Antigens; D005353:Fibronectins; D037181:Lectins, C-Type; D016169:Lymphocyte Function-Associated Antigen-1; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D011971:Receptors, Immunologic; D007371:Interferon-gamma