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* Department of Microbiology and Immunology and
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461;
Children’s Hospital and Harvard Medical School, Boston, MA 02115; and
Department of Molecular Genetics and Biochemistry and Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
The chemokine receptor CXCR3 plays a significant role in regulating the migration of Th1 cells. Given the importance of Th1 immunity in the control of tuberculous infection, the results of the present study demonstrating that CXCR3-deficient BALB/c mice are more resistant to Mycobacterium tuberculosis, compared with wild-type mice, is surprising. This enhanced resistance manifests in the chronic but not the acute phase of infection. Remarkable differences in the cellular composition of the pulmonic granuloma of the CXCR3–/– and wild-type mice were found, the most striking being the increase in the number of CD4+ T cells in the knockout strain. In the chronic phase of infection, the number of CD69-expressing CD4+ T lymphocytes in the lungs of CXCR3–/– mice was higher than in wild-type mice. Additionally, at 1 mo postinfection, the number of IFN-
-producing CD4+ T cells in the lungs and mediastinal lymph nodes of the CXCR3-deficient strain was elevated compared with wild-type mice. Pulmonic expression of IFN-, IL-12, TNF-
, or NO synthase 2, the principal antimycobacterial factors, were equivalent in the two mouse strains. These results indicate that: 1) CXCR3 plays a role in modulating the cellular composition of tuberculous granuloma; 2) CXCR3 impairs antimycobacterial activity in chronic tuberculosis; and 3) in the absence of CXCR3, mice exhibit a heightened state of CD4+ T lymphocyte activation in the chronic phase of infection that is associated with enhanced CD4+ T cell priming. Therefore, CXCR3 can attenuate the host immune response to M. tuberculosis by adversely affecting T cell priming.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI50732, AI63537, HL71241, and T32 GM007288 and the Albert Einstein College of Medicine Grant CFAR P30 AI51519. Data presented here are part of a thesis (S.D.C.) submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Sue Golding Graduate Division of Medical Sciences, Albert Einstein College of Medicine, Yeshiva University.
2 Address correspondence and reprint requests to Dr. John Chan, Departments of Medicine and Microbiology & Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue F406, Bronx, NY 10461. E-mail address: jchan{at}aecom.yu.edu
3 Abbreviations used in this paper: MLN, mediastinal lymph node; LCM, laser capture microdissection; NOS2, NO synthase 2; Treg, regulatory T cell.
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