TGF-beta 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-beta1 production, as assessed either by CTLA-4 blockade or by direct CTLA-4 cross-linkage. Production of TGF-beta1 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-beta1 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-beta1 Ab. Exogenous addition of rTGF-beta1 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.
Gomes
N A
NA
Immunobiology Program, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Gattass
C R
CR
Barreto-De-Souza
V
V
Wilson
M E
ME
DosReis
G A
GA
D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007106:Immune Sera / Q000494:pharmacology; D007111:Immunity, Cellular / Q000276:immunology; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018314:Leishmania infantum / Q000254:growth & development / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018984:Epitopes, T-Lymphocyte; D007106:Immune Sera; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D000069594:Abatacept