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PMID: 12874328 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The Mycobacterium tuberculosis 19-kilodalton lipoprotein inhibits gamma interferon-regulated HLA-DR and Fc gamma R1 on human macrophages through Toll-like receptor 2.

Infection and immunity ·Vol. 71 ·No. 8 ·2003-08-00 ·Pages 4487-97

Gehring AJ, Rojas RE, Canaday DH, Lakey DL, Harding CV, Boom WH

Abstract

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.

MeSH Terms
Animals Antibodies, Monoclonal/pharmacology Antigen Presentation/drug effects Apoptosis/drug effects Bacterial Proteins/toxicity Base Sequence Cell Line Gene Expression/drug effects HLA-DR Antigens/genetics,metabolism Humans Hybridomas/immunology Interferon-gamma/metabolism Lipoproteins/toxicity Macrophages/drug effects,immunology Membrane Glycoproteins/antagonists & inhibitors,metabolism Mice Mice, Transgenic Mycobacterium tuberculosis/genetics,immunology,pathogenicity,physiology RNA, Messenger/genetics,metabolism Receptors, Cell Surface/antagonists & inhibitors,metabolism Receptors, IgG/metabolism Receptors, Interferon/drug effects,metabolism Signal Transduction/drug effects Toll-Like Receptor 2 Toll-Like Receptors
Chemicals
Antibodies, Monoclonal Bacterial Proteins HLA-DR Antigens Lipoproteins Membrane Glycoproteins RNA, Messenger Receptors, Cell Surface Receptors, IgG Receptors, Interferon TLR2 protein, human Toll-Like Receptor 2 Toll-Like Receptors interferon gamma receptor Interferon-gamma
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Gehring Adam J
Department of Pathology, Division of Infectious Disease, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106-4984, USA.
Rojas Roxana E
Canaday David H
Lakey David L
Harding Clifford V
Boom W Henry
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Article Info
Journal
Infection and immunity
Abbr.
Infect Immun
ISSN
0019-9567
DOI
10.1128/IAI.71.8.4487-4497.2003
Published
2003-08-00
Pages
4487-97
Language
English
Region
United States
NLM ID
0246127
PMCID
PMC166015
Subset
IM
Grants
NIAID NIH HHS · AI27243 · United States
NIAID NIH HHS · R01 AI035726 · United States
NHLBI NIH HHS · HL55967 · United States
NIAID NIH HHS · R01 AI034343 · United States
NIAID NIH HHS · R01 AI027243 · United States
NIAID NIH HHS · AI47255 · United States
NIAID NIH HHS · R01 AI047255 · United States
NIAID NIH HHS · N01AI95383 · United States
NIAID NIH HHS · AI35726 · United States
NHLBI NIH HHS · R01 HL055967 · United States
NIAID NIH HHS · AI34343 · United States
External Links
PubMed source DOI: 10.1128/IAI.71.8.4487-4497.2003 PMC Full Text View journal details
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