The Mycobacterium tuberculosis 19-kilodalton lipoprotein inhibits gamma interferon-regulated HLA-DR and Fc gamma R1 on human macrophages through Toll-like receptor 2.
Mycobacterium tuberculosis survives in macrophages in the face of acquired CD4(+) T-cell immunity, which controls but does not eliminate the organism. Gamma interferon (IFN-gamma) has a central role in host defenses against M. tuberculosis by activating macrophages and regulating major histocompatibility complex class II (MHC-II) antigen (Ag) processing. M. tuberculosis interferes with IFN-gamma receptor (IFN-gamma R) signaling in macrophages, but the molecules responsible for this inhibition are poorly defined. This study determined that the 19-kDa lipoprotein from M. tuberculosis inhibits IFN-gamma-regulated HLA-DR protein and mRNA expression in human macrophages. Inhibition of HLA-DR expression was associated with decreased processing and presentation of soluble protein Ags and M. tuberculosis bacilli to MHC-II-restricted T cells. Inhibition of HLA-DR required prolonged exposure to 19-kDa lipoprotein and was blocked with a monoclonal antibody specific for Toll-like receptor 2 (TLR-2). The 19-kDa lipoprotein also inhibited IFN-gamma-induced expression of Fc gamma RI. Thus, M. tuberculosis, through 19-kDa lipoprotein activation of TLR-2, inhibits IFN-gamma R signaling in human macrophages, resulting in decreased MHC-II Ag processing and recognition by MHC-II-restricted CD4 T cells. These findings provide a mechanism for M. tuberculosis persistence in macrophages.
Gehring
Adam J
AJ
Department of Pathology, Division of Infectious Disease, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106-4984, USA.
Rojas
Roxana E
RE
Canaday
David H
DH
Lakey
David L
DL
Harding
Clifford V
CV
Boom
W Henry
WH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017951:Antigen Presentation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000633:toxicity*; D001483:Base Sequence; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D008074:Lipoproteins / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D017471:Receptors, Interferon / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D000096743:Interferon gamma Receptor
D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D006684:HLA-DR Antigens; D007371:Interferon-gamma; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D017471:Receptors, Interferon; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D000096743:Interferon gamma Receptor; C495342:TLR2 protein, human