Inhibition of caspase-8 activity promotes protective Th1- and Th2-mediated immunity to Leishmania major infection.
We investigated how apoptosis pathways mediated by death receptors and caspase-8 affect cytokine responses and immunity to Leishmania major parasites. Splenic CD4 T cells undergo activation-induced apoptosis, and blockade of FasL-Fas interaction increased IFN-γ and IL-4 cytokine responses to L. major antigens. To block death receptor-induced death, we used mice expressing a T cell-restricted transgene for vFLIP. Inhibition of caspase-8 activation in vFLIP mice enhanced Th1 and Th2 cytokine responses to L. major infection, even in the Th1-prone B6 background. We also observed increased NO production by splenocytes from vFLIP mice upon T cell activation. Despite an exacerbated Th2 response, vFLIP mice controlled better L. major infection, with reduced lesions and lower parasite loads compared with WT mice. Moreover, injection of anti-IL-4 mAb in infected vFLIP mice disrupted control of parasite infection. Therefore, blockade of caspase-8 activity in T cells improves immunity to L. major infection by promoting increased Th1 and Th2 responses.
5.Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho 373, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil. marcelal@biof.ufrj.br.
Wânia F
WF
Pereira-Manfro
Flávia L
FL
Ribeiro-Gomes
Alessandra Almeida
AA
Filardy
Natália S
NS
Vellozo
Landi V C
LV
Guillermo
Elisabeth M
EM
Silva
Richard M
RM
Siegel
George A
GA
Dosreis
Marcela F
MF
Lopes
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D015847:Interleukin-4 / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology*; D007896:Leishmaniasis / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology
D000953:Antigens, Protozoan; D014764:Viral Proteins; D015847:Interleukin-4; D053181:Caspase 8
CD4 T cells; FLIP; FasL; apoptosis; cytokines