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

Citation
Na. Gomes et al., TGF-beta mediates CTLA-4 suppression of cellular immunity in murine kalaazar, J IMMUNOL, 164(4), 2000, pp. 2001-2008
Citations number
37
Categorie Soggetti
Immunology
Journal title
JOURNAL OF IMMUNOLOGY
ISSN journal
00221767 → ACNP
Volume
164
Issue
4
Year of publication
2000
Pages
2001 - 2008
Database
ISI
SICI code
0022-1767(20000215)164:4<2001:TMCSOC>2.0.ZU;2-#
Abstract
Recent studies indicate important roles for CTLA-4 engagement in T cells, a nd 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 o r 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-be ta 1 accounted for the reciprocal regulation of IFN-gamma production by CTL A-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 increas ed L, chagasi replication in cocultures of infected macrophages and activat ed CD4(+) T cells, and parasite growth could be completely blocked with neu tralizing anti-TGF-beta 1 Ab, Exogenous addition of rTGF-beta 1 restored pa rasite growth in cultures protected from parasitism by CTLA-4 blockade. The se results indicate that the negative costimulatory receptor CTLA-4 is crit ically involved in TGF-beta production and in intracellular parasite replic ation seen in murine kalaazar.