The Journal of Immunology, Vol 153, Issue 11 5190-5199, Copyright © 1994 by American Association of Immunologists

ARTICLES

Regulation of T helper cell responses in experimental murine schistosomiasis by IL-10. Effect on expression of B7 and B7-2 costimulatory molecules by macrophages

PO Flores Villanueva, H Reiser and MJ Stadecker
Department of Pathology, Tufts University School of Medicine, Boston, MA 02111.

Granulomatous inflammation in schistosomiasis is a manifestation of cell-mediated hypersensitivity to parasite egg Ags that is predictably reduced in size over the course of the disease. This down-regulation may reflect a state of anergy in the T cells mediating granuloma formation after interaction with accessory cells incapable of providing full stimulation. The present studies were conducted to investigate this mechanism at the molecular level. We found that granuloma macrophages (GM) strongly inhibit the ability of splenic APC to stimulate egg Ag-specific Th1 responses. This property was shown to be dependent on their secretion of IL-10. Moreover, activated GM in culture were found to express little or no costimulatory Ags B7 or B7- 2. However, when their autocrine secretion of IL-10 was neutralized with specific mAb, GM displayed an up-regulation of costimulatory molecules as well as of MHC class II Ags. Most importantly, GM cultured in the presence of anti-IL-10 mAb, acquired the ability to stimulate egg Ag-specific T cells. By independently blocking each of the induced costimulatory Ags, it appeared that B7-2 molecules provided stronger costimulation than B7. In separate experiments, culture supernatants from GM exerted a powerful inhibition of costimulatory Ag expression on Con-A-stimulated peritoneal exudate cells in vivo, which could similarly be attributed to IL-10. Our results demonstrate that IL-10 can play a critical role in the generation of accessory cells that, by virtue of down-regulation of costimulatory molecules, may be capable of inducing anergy in T cells mediating the vigorous granulomatous response of acute stage schistosomiasis. Our studies lend support to the contention that a state of unresponsiveness in pathogenic T cells may precipitate the down-regulation of granuloma formation and provide a molecular basis for the underlying mechanisms.

This article has been cited by other articles:

				N. E. Mangan, R. E. Fallon, P. Smith, N. van Rooijen, A. N. McKenzie, and P. G. Fallon Helminth Infection Protects Mice from Anaphylaxis via IL-10-Producing B Cells J. Immunol., November 15, 2004; 173(10): 6346 - 6356. [Abstract] [Full Text] [PDF]

				P. Smith, C. M. Walsh, N. E. Mangan, R. E. Fallon, J. R. Sayers, A. N. J. McKenzie, and P. G. Fallon Schistosoma mansoni Worms Induce Anergy of T Cells via Selective Up-Regulation of Programmed Death Ligand 1 on Macrophages J. Immunol., July 15, 2004; 173(2): 1240 - 1248. [Abstract] [Full Text] [PDF]

				N. G. Sandler, M. M. Mentink-Kane, A. W. Cheever, and T. A. Wynn Global Gene Expression Profiles During Acute Pathogen-Induced Pulmonary Inflammation Reveal Divergent Roles for Th1 and Th2 Responses in Tissue Repair J. Immunol., October 1, 2003; 171(7): 3655 - 3667. [Abstract] [Full Text] [PDF]

				L. I. Rutitzky, E. Ozkaynak, J. B. Rottman, and M. J. Stadecker Disruption of the ICOS-B7RP-1 Costimulatory Pathway Leads to Enhanced Hepatic Immunopathology and Increased Gamma Interferon Production by CD4 T Cells in Murine Schistosomiasis Infect. Immun., July 1, 2003; 71(7): 4040 - 4044. [Abstract] [Full Text] [PDF]

				L. I. Rutitzky, H. J. Hernandez, and M. J. Stadecker Th1-polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection PNAS, October 16, 2001; (2001) 231258498. [Abstract] [Full Text] [PDF]

				D. O. Beenhouwer, S. Shapiro, M. Feldmesser, A. Casadevall, and M. D. Scharff Both Th1 and Th2 Cytokines Affect the Ability of Monoclonal Antibodies To Protect Mice against Cryptococcus neoformans Infect. Immun., October 1, 2001; 69(10): 6445 - 6455. [Abstract] [Full Text] [PDF]

				J. P. Justice, Y. Shibata, S. Sur, J. Mustafa, M. Fan, and M. R. Van Scott IL-10 gene knockout attenuates allergen-induced airway hyperresponsiveness in C57BL/6 mice Am J Physiol Lung Cell Mol Physiol, February 1, 2001; 280(2): L363 - L368. [Abstract] [Full Text] [PDF]

				J. A. Cain and G. S. Deepe Jr. Interleukin-12 Neutralization Alters Lung Inflammation and Leukocyte Expression of CD80, CD86, and Major Histocompatibility Complex Class II in Mice Infected with Histoplasma capsulatum Infect. Immun., April 1, 2000; 68(4): 2069 - 2076. [Abstract] [Full Text] [PDF]

				A. S. Varadhachary, M. E. Peter, S. N. Perdow, P. H. Krammer, and P. Salgame Selective Up-Regulation of Phosphatidylinositol 3'-Kinase Activity in Th2 Cells Inhibits Caspase-8 Cleavage at the Death-Inducing Complex: A Mechanism for Th2 Resistance from Fas-Mediated Apoptosis J. Immunol., November 1, 1999; 163(9): 4772 - 4779. [Abstract] [Full Text] [PDF]

				D. L. Foss, M. J. Zilliox, and M. P. Murtaugh Differential Regulation of Macrophage Interleukin-1 (IL-1), IL-12, and CD80-CD86 by Two Bacterial Toxins Infect. Immun., October 1, 1999; 67(10): 5275 - 5281. [Abstract] [Full Text] [PDF]

				D. L. Boros and J. R. Whitfield Enhanced Th1 and Dampened Th2 Responses Synergize To Inhibit Acute Granulomatous and Fibrotic Responses in Murine Schistosomiasis Mansoni Infect. Immun., March 1, 1999; 67(3): 1187 - 1193. [Abstract] [Full Text] [PDF]

				H. J. Hernandez, A. H. Sharpe, and M. J. Stadecker Experimental Murine Schistosomiasis in the Absence of B7 Costimulatory Molecules: Reversal of Elicited T Cell Cytokine Profile and Partial Inhibition of Egg Granuloma Formation J. Immunol., March 1, 1999; 162(5): 2884 - 2889. [Abstract] [Full Text] [PDF]

				A. Mencacci, E. Cenci, G. D. Sero, C. Fe d'Ostiani, P. Mosci, G. Trinchieri, L. Adorini, and L. Romani IL-10 Is Required for Development of Protective Th1 Responses in IL-12-Deficient Mice upon Candida albicans Infection J. Immunol., December 1, 1998; 161(11): 6228 - 6237. [Abstract] [Full Text] [PDF]

				J. Fierer, L. Walls, L. Eckmann, T. Yamamoto, and T. N. Kirkland Importance of Interleukin-10 in Genetic Susceptibility of Mice to Coccidioides immitis Infect. Immun., September 1, 1998; 66(9): 4397 - 4402. [Abstract] [Full Text] [PDF]

				E. Rakasz, A. M. Blum, A. Metwali, D. E. Elliott, J. Li, Z. K. Ballas, K. Qadir, R. Lynch, and J. V. Weinstock Localization and Regulation of IFN-{gamma} Production Within the Granulomas of Murine Schistosomiasis in IL-4-Deficient and Control Mice J. Immunol., May 15, 1998; 160(10): 4994 - 4999. [Abstract] [Full Text] [PDF]

				T. A. Wynn, A. W. Cheever, M. E. Williams, S. Hieny, P. Caspar, R. Kuhn, W. Muller, and A. Sher IL-10 Regulates Liver Pathology in Acute Murine Schistosomiasis mansoni But Is Not Required for Immune Down-Modulation of Chronic Disease J. Immunol., May 1, 1998; 160(9): 4473 - 4480. [Abstract] [Full Text] [PDF]

				D. Jankovic, A. W. Cheever, M. C. Kullberg, T. A. Wynn, G. Yap, P. Caspar, F. A. Lewis, R. Clynes, J. V. Ravetch, and A. Sher CD4+ T Cell-mediated Granulomatous Pathology in Schistosomiasis Is Downregulated by a B Cell-dependent Mechanism Requiring Fc Receptor Signaling J. Exp. Med., February 16, 1998; 187(4): 619 - 629. [Abstract] [Full Text] [PDF]

				A. S. Varadhachary, S. N. Perdow, C. Hu, M. Ramanarayanan, and P. Salgame Differential ability of T cell subsets to undergo activation-induced cell death PNAS, May 27, 1997; 94(11): 5778 - 5783. [Abstract] [Full Text] [PDF]

				H. Reiser and M. J. Stadecker Costimulatory B7 Molecules in the Pathogenesis of Infectious and Autoimmune Diseases N. Engl. J. Med., October 31, 1996; 335(18): 1369 - 1377. [Full Text] [PDF]

				L. I. Rutitzky, H. J. Hernandez, and M. J. Stadecker Th1-polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection PNAS, November 6, 2001; 98(23): 13243 - 13248. [Abstract] [Full Text] [PDF]