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TGF-ß Mediates CTLA-4 Suppression of Cellular Immunity in Murine Kalaazar¹

Nitza A. Gomes^*, Cerli R. Gattass^*, Victor Barreto-de-Souza^*, Mary E. Wilson and George A. DosReis^2,*

^* Immunobiology Program, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; and Departments of Internal Medicine and Microbiology, University of Iowa, Iowa City, IA 52242

Recent studies indicate important roles for CTLA-4 engagement in T cells, and for TGF-ß production in the immunopathogenesis of murine kalaazar or visceral leishmaniasis, but a functional link between these two pathways in helping intracellular parasite growth is unknown. Here we report that Ag or anti-CD3 activation of splenic CD4⁺ T cells from visceral leishmaniasis leads to intense CTLA-4-mediated TGF-ß1 production, as assessed either by CTLA-4 blockade or by direct CTLA-4 cross-linkage. Production of TGF-ß1 accounted for the reciprocal regulation of IFN- production by CTLA-4 engagement. Following CD4⁺ T cell activation, intracellular growth of Leishmania chagasi in cocultured splenic macrophages required both CTLA-4 function and TGF-ß1 secretion. Cross-linkage of CTLA-4 markedly increased L. chagasi replication in cocultures of infected macrophages and activated CD4⁺ T cells, and parasite growth could be completely blocked with neutralizing anti-TGF-ß1 Ab. Exogenous addition of rTGF-ß1 restored parasite growth in cultures protected from parasitism by CTLA-4 blockade. These results indicate that the negative costimulatory receptor CTLA-4 is critically involved in TGF-ß production and in intracellular parasite replication seen in murine kalaazar.