TGF-β mediates CTLA-4 suppression of cellular immunity in murine kalaazar

Recent studies indicate important roles for CTLA-4 engagement in T cells, and for TGF-beta 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-beta 1 production, as assessed either by CTLA-4 blockade or by direct CTLA-4 cross-linkage. Production of TGF-beta 1 accounted for the reciprocal regulation of IFN-gamma 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-beta 1 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-beta 1 Ab, Exogenous addition of rTGF-beta 1 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-beta production and in intracellular parasite replication seen in murine kalaazar.