Unresponsive CD4⁺T Lymphocytes fromLeishmania chagasi–Infected Mice Increase Cytokine Production and Mediate Parasite Killing after Blockade of B7‐1/CTLA‐4 Molecular Pathway

Abstract

Infection of BALB/c mice with Leishmania chagasi results in progressive increase of parasite burden in spleen, in spite of extensive T cell activation in situ. Explanted splenic CD4+ T cells showed decreased proliferation to anti-CD3, compared with controls, and no response to L. chagasi recombinant antigen Lcr1. Blockade of the negative costimulatory receptor CTLA-4 restored responses to anti-CD3 and induced vigorous responses to Lcr1. Blockade of B7-1, but not B7-2, also enhanced T cell responsiveness. CTLA-4 blockade completely restored activation-induced interleukin-2 secretion and increased interferon-gamma production. The effect, however, was not restricted to Th1 responses, since CTLA-4 blockade also enhanced antigen-induced interleukin-4 secretion. CTLA-4 blockade induced almost complete elimination of parasite burden in splenocyte cultures activated with anti-CD3 or Lcr1. These results indicate that CTLA-4 engagement by B7-1 plays an important role in maintaining unresponsiveness in CD4+ T cells in this model of chronic visceral leishmaniasis.

Modulation of T-Cell Costimulation as Immunotherapy or Immunochemotherapy in Experimental Visceral Leishmaniasis

“…While anti-CTLA-4 treatment produces variable effects and can exacerbate cutaneous L. major infection (10,15), anti-CTLA-4 is active both prophylactically and therapeutically against visceral L. donovani infection (20). In vitro studies with L. chagasi, another agent of visceral leishmaniasis, also support the antileishmanial effect of MAb blockade of either T-cell-expressed CTLA-4 or its B7 ligands on APC (10,11).…”

“…An alternative strategy to therapeutically harness the same Th1 cell mechanism has focused on T-cell costimulation (7,11,19,20). Optimal T-cell activation, including induction of the antileishmanial Th1 response with secretion of IL-12, IL-2, and IFN-␥, requires second (costimulatory) signals likely delivered via interaction of surface molecules on T cells and antigenpresenting cells (APC) (7,11,19,20,39,41).…”

“…Optimal T-cell activation, including induction of the antileishmanial Th1 response with secretion of IL-12, IL-2, and IFN-␥, requires second (costimulatory) signals likely delivered via interaction of surface molecules on T cells and antigenpresenting cells (APC) (7,11,19,20,39,41). CD40 ligand [CD40L]-CD40 and CD28-B7 represent two such signal-transducing receptor pathways (38,40), active in various forms of experimental leishmaniasis (3,4,10,11,14,15,17,32,37,38) and accessible to manipulation by MAb injection (7,15,(18)(19)(20). Depending upon the model, the host, and the timing of MAb administration, receptor manipulation can stimulate Th1 type responses and enhance resistance.…”

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

“…Recently, the negative costimulatory T-cell receptor CTLA-4 has been characterized as an important negative regulator of T-cell activation (Waterhouse et al 1995). We found that antibody-mediated blockade of either CTLA-4 or its ligand B7-1, restored otherwise suppressed T-cell responses, increased IFN-γ production, and promoted rapid killing of L. chagasi parasites within splenic Mφ (Gomes et al 1998). 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).…”

“…In this disease, the splenic load of L. chagasi increases indefinitely, and local CD4 + T cells are unresponsive to mitogen or leishmanial antigen stimulation, but do not undergo AICD (Gomes et al 1998). Recently, the negative costimulatory T-cell receptor CTLA-4 has been characterized as an important negative regulator of T-cell activation (Waterhouse et al 1995).…”