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 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.
Gomes
N A
NA
Immunobiology Program, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Jameiro, Brazil.
Barreto-de-Souza
V
V
Wilson
M E
ME
DosReis
G A
GA
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D018122:B7-1 Antigen / Q000502:physiology*; D017252:CD3 Complex / Q000276:immunology; D060908:CTLA-4 Antigen; D002908:Chronic Disease; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007896:Leishmaniasis / Q000276:immunology*; D008213:Lymphocyte Activation; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D007376:Interleukin-2; D015847:Interleukin-4; D000069594:Abatacept