Unresponsive CD4(+) T lymphocytes from Leishmania chagasi-infected mice increase cytokine production and mediate parasite killing after blockade of B7-1/CTLA-4 molecular pathway

Infection of BALB/c mice with Leishmania chagasi results in progressive inc rease of parasite burden in spleen, in spite of extensive T cell activation in situ, Explanted splenic CD4(+) T cells showed decreased proliferation t o anti-CD3, compared with controls, and no response to L. chagasi recombina nt antigen Lcr1, Blockade of the negative costimulatory receptor CTLA-4 res tored responses to anti-CD3 and induced vigorous responses to Lcr1. Blockad e of B7-1, but not B7-2, also enhanced T cell responsiveness. CTLA-4 blocka de completely restored activation-induced interleukin-2 secretion and incre ased interferon-gamma production, The effect, however, was not restricted t o Th1 responses, since CTLA-4 blockade also enhanced antigen-induced interl eukin-4 secretion. CTLA-4 blockade induced almost complete elimination of p arasite burden in splenocyte cultures activated with anti-CDS or Lcr1, Thes e results indicate that CTLA-4 engagement by B7-1 plays an important role i n maintaining unresponsiveness in CD4(+) T cells in this model of chronic v isceral leishmaniasis.