Mycobacterium bovis BCG-induced granuloma formation depends on gamma interferon and CD40 ligand but does not require CD28.
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.
Hogan
L H
LH
Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, Madison, Wisconsin, USA. lhhogan@facstaff.wisc.edu
Markofski
W
W
Bock
A
A
Barger
B
B
Morrissey
J D
JD
Sandor
M
M
D000818:Animals; D018106:CD28 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology*; D006099:Granuloma / Q000209:etiology* / Q000473:pathology; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000502:physiology*; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis; D013601:T-Lymphocytes / Q000502:physiology; D014376:Tuberculosis / Q000276:immunology* / Q000473:pathology
D018106:CD28 Antigens; D023201:CD40 Ligand; D007371:Interferon-gamma