The Journal of Experimental Medicine
VeriKine-HS Human Interferon-Beta Serum
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Published online 7 August 2000.
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© The Rockefeller University Press, 0022-1007/2000/8/347/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 3, August 7, 2000 347-358

Original Article

Depletion of Cd4+ T Cells Causes Reactivation of Murine Persistent Tuberculosis despite Continued Expression of Interferon {gamma} and Nitric Oxide Synthase 2

Charles A. Scangaa, V.P. Mohanc,d, Keming Yuc,d, Heather Josepha, Kathryn Tanakae, John Chanc,d, and JoAnne L. Flynna,b

a Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
b Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
c Department of Medicine, Montefiore Hospital and Albert Einstein College of Medicine, Bronx, New York 10461
d Department of Microbiology and Immunology, Montefiore Hospital and Albert Einstein College of Medicine, Bronx, New York 10461
e Department of Pathology, Montefiore Hospital and Albert Einstein College of Medicine, Bronx, New York 10461
Dept. of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1240 Biomedical Science Tower, Pittsburgh, PA 15261.412-624-1401412-624-7743

joanne{at}pitt.edu

Tuberculosis is a major cause of death in much of the world. Current estimates are that one-third of the world's population is infected with Mycobacterium tuberculosis. Most infected persons control the infection but in many cases may not eliminate the organism. Reactivation of this clinically latent infection is responsible for a large proportion of active tuberculosis cases. A major risk factor for reactivation of latent tuberculosis is HIV infection, suggesting a role for the CD4+ T cell subset in maintaining the latent persistent infection. In this study, we tested the requirement for CD4+ T cells in preventing reactivation in a murine model of latent tuberculosis. Antibody-mediated depletion of CD4+ T cells resulted in rapid reactivation of a persistent infection, with dramatically increased bacterial numbers in the organs, increased pathology in the lungs, and decreased survival. Although CD4+ T cells are believed to be a major source of interferon (IFN)-{gamma}, expression of the gene for IFN-{gamma} in the lungs of CD4+ T cell–depleted mice was similar to that in control mice. In addition, inducible nitric oxide synthase production and activity was unimpaired after CD4+ T cell depletion, indicating that macrophage activation was present even during CD4+ T cell deficiency. These data indicate that CD4+ T cells are necessary to prevent reactivation but may have roles in addition to IFN-{gamma} production and macrophage activation in controlling a persistent tuberculous infection.

Key Words: Mycobacterium tuberculosis • bacterial infection • macrophage • lung • nitric oxide synthase

Abbreviations used in this paper: NOS, nitric oxide synthase; RNIs, reactive nitrogen intermediates; RPA, ribonuclease protection assay.

C.A. Scanga and V.P. Mohan contributed equally to this study.

Address correspondence to John Chan, Dept. of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: 718-430-2678; Fax: 718-652-0536; E-mail: jchan{at}aecom.yu.edu

© 2000 The Rockefeller University Press


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