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Infection and Immunity, August 2003, p. 4487-4497, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4487-4497.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Mycobacterium tuberculosis 19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Regulated HLA-DR and Fc{gamma}R1 on Human Macrophages through Toll-Like Receptor 2

Adam J. Gehring,1,2 Roxana E. Rojas,2 David H. Canaday,2 David L. Lakey,3 Clifford V. Harding,1 and W. Henry Boom2,4*

Department of Pathology,1 Division of Infectious Disease,2 Tuberculosis Research Unit, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio,4 Division of Infectious Disease, Center for Pulmonary and Infectious Disease Control, University of Texas Health Center at Tyler, Tyler, Texas3

Received 18 March 2003/ Accepted 15 May 2003

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.

* Corresponding author. Mailing address: Division of Infectious Disease, BRB 1031, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4984. Phone: (216) 368-4844. Fax: (216) 368-2034. E-mail: WHB{at}cwru.edu.

Editor: S. H. E. Kaufmann

Infection and Immunity, August 2003, p. 4487-4497, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4487-4497.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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