TGF-β Mediates CTLA-4 Suppression of Cellular Immunity in Murine Kalaazar

Abstract

Recent studies indicate important roles for CTLA-4 engagement in T cells, and for TGF-β 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-β1 production, as assessed either by CTLA-4 blockade or by direct CTLA-4 cross-linkage. Production of TGF-β1 accounted for the reciprocal regulation of IFN-γ 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-β1 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-β1 Ab. Exogenous addition of rTGF-β1 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-β production and in intracellular parasite replication seen in murine kalaazar.

Murine Malaria Is Exacerbated by CTLA-4 Blockade

“…In the spleen, the number of CD4 ϩ cells decreased by Ͼ50%, and CD4 ϩ cells analyzed ex vivo did neither proliferate spontaneously nor in response to anti-CD3. Treatment of such spleen cells from infected mice with anti-TGF-␤ did not restore immune suppression (data not shown), suggesting that TGF-␤ production by CTLA-4-positive cells is not linked to immune suppression in P. berghei malaria, as it was described for Leishmania infections (27).…”

“…CTLA-4 may also antagonize CD28 function by competing for B7 molecules, or by inhibiting CD28-mediated TCR reorganization. Finally, CTLA-4 triggering has been reported to induce the production of TGF-␤ (27). The effect of CTLA-4 blockade in vivo was first demonstrated in a tumor model in which an enhanced antitumor immunity was observed (19).…”

“…The effect of CTLA-4 blockade in vivo was first demonstrated in a tumor model in which an enhanced antitumor immunity was observed (19). Several studies have shown that blocking of CTLA-4 ligation also improved adaptive immune response against various infectious agents, leading to an enhanced clearance of pathogens (20,27). However, in mycobacterial infections, an increased immune response was induced, but did not influence the course of infection (18).…”

Susceptible hosts: a resort for parasites right in the eye of the immune response

“…Although the mechanisms of CTLA-4 suppression of T-cell activation are still undefined, a recent study demonstrated that engagement of CTLA-4 promotes the production of TGF-β by CD4 + T cells, while inhibiting the production of all other cytokines tested (Chen et al 1998). We found that splenic CD4 + T cells from kalazar secrete large amounts of TGF-β when stimulated by Leishmania antigen or mitogens, and that TGF-β secretion can be abolished by CTLA-4 blockade (Gomes et al 2000). Moreover, we demonstrated that CTLA-4 engagement suppresses T-cell IFN-γ production and promotes L. chagasi growth in cocultured Mφ through secretion of TGF-β (Gomes et al 2000).…”

“…We found that splenic CD4 + T cells from kalazar secrete large amounts of TGF-β when stimulated by Leishmania antigen or mitogens, and that TGF-β secretion can be abolished by CTLA-4 blockade (Gomes et al 2000). Moreover, we demonstrated that CTLA-4 engagement suppresses T-cell IFN-γ production and promotes L. chagasi growth in cocultured Mφ through secretion of TGF-β (Gomes et al 2000). These results suggest that L. chagasi infection induces host T cells to produce TGF-β by driving them to a state of sustained CTLA-4 engagement.…”