Caspase-8 activity prevents type 2 cytokine responses and is required for protective T cell-mediated immunity against Trypanosoma cruzi infection.
During Trypanosoma cruzi infection, T cells up-regulate caspase-8 activity. To assess the role of caspase-8 in T cell-mediated immunity, we investigated the effects of caspase-8 inhibition on T cells in viral FLIP (v-FLIP) transgenic mice. Compared with wild-type controls, increased parasitemia was observed in v-FLIP mice infected with T. cruzi. There was a profound decrease in expansion of both CD4 and CD8 T cell subsets in the spleens of infected v-FLIP mice. We did not find differences in activation ratios of T cells from transgenic or wild-type infected mice. However, the numbers of memory/activated CD4 and CD8 T cells were markedly reduced in v-FLIP mice, possibly due to defective survival. We also found decreased production of IL-2 and increased secretion of type 2 cytokines, IL-4 and IL-10, which could enhance susceptibility to infection. Similar, but less pronounced, alterations were observed in mice treated with the caspase-8 inhibitor, zIETD. Furthermore, blockade of caspase-8 by zIETD in vitro mimicked the effects observed on T. cruzi infection in vivo, affecting the generation of activated/memory T cells and T cell cytokine production. Caspase-8 is also required for NF-kappaB signaling upon T cell activation. Blockade of caspase-8 by either v-FLIP expression or treatment with zIETD peptide decreased NF-kappaB responses to TCR:CD3 engagement in T cell cultures. These results suggest a critical role for caspase-8 in the establishment of T cell memory, cell signaling, and regulation of cytokine responses during protozoan infection.
Silva
Elisabeth M
EM
Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Bloco G, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Guillermo
Landi V C
LV
Ribeiro-Gomes
Flávia L
FL
De Meis
Juliana
J
Pereira
Renata M S
RM
Wu
Zhengqi
Z
Calegari-Silva
Teresa C
TC
Seabra
Sérgio H
SH
Lopes
Ulisses G
UG
Siegel
Richard M
RM
Dosreis
George A
GA
Lopes
Marcela F
MF
D000818:Animals; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000096:biosynthesis / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D014355:Chagas Disease / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D007111:Immunity, Cellular / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000494:pharmacology; D018418:Th2 Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics
D061945:Caspase Inhibitors; D016207:Cytokines; D009842:Oligopeptides; D014764:Viral Proteins; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone; C481275:viral FLIP protein, Human herpesvirus 8; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases