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*
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.
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