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Infection and Immunity, April 2001, p. 2596-2603, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2596-2603.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Mycobacterium bovis BCG-Induced Granuloma Formation Depends on Gamma Interferon and CD40 Ligand but Does Not Require CD28

Laura H. Hogan,* Wes Markofski, Anja Bock,dagger Brittany Barger, James D. Morrissey, and Matyas Sandor

Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, Madison, Wisconsin

Received 28 September 2000/Returned for modification 6 December 2000/Accepted 4 January 2001

Progressive granuloma formation is a hallmark of chronic mycobacterial infection. Granulomas are localized, protective inflammatory reactions initiated by CD4+ T cells, which contribute to control of bacterial growth and blockade of bacterial dissemination. In order to understand the costimulatory requirements that allow CD4+ T cells to directly or indirectly induce granulomas, we studied granuloma formation after 6 weeks in Mycobacterium bovis BCG-infected CD28- and CD40 ligand (CD40L)-deficient mice and compared it to granuloma formation in infected wild-type inbred mice and infected cytokine-deficient mice. We characterized granulomas morphologically in liver sections, analyzed granuloma infiltrating cells by flow cytometry, and measured cytokine production by cultured granuloma cells. CD28-deficient mice have no defect at the local inflammatory site, inasmuch as they form protective granulomas and control bacterial growth. However, there are fewer activated T cells in the spleen compared to infected wild-type animals, and quantitative differences in the cellular composition of the granuloma are observed by flow cytometry. In CD40L-deficient mice, the granuloma phenotype is very similar to the phenotype in gamma interferon (IFN-gamma )-deficient mice. Both IFN-gamma -deficient and CD40L-deficient mice form granulomas which prevent bacterial dissemination, but control of bacterial growth is significantly impaired. The relative proportion of CD4+ T cells in granulomas from both CD28-/- and CD40L-/- mice is significantly decreased compared with wild-type animals. Both models demonstrate that the phenotype and activation stage of systemic T cells do not always correlate with the phenotype and activation stage of the localized granulomatous response.

* Corresponding author. Mailing address: Room 5580 MSC, 1300 University Ave., Madison, WI 53706. Phone: (608) 262-2577. Fax: (608) 265-3301. E-mail: lhhogan{at}facstaff.wisc.edu.

dagger Present address: University of Heidelberg, Heidelberg, Germany.

Infection and Immunity, April 2001, p. 2596-2603, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2596-2603.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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