Caspase-8 Activity Prevents Type 2 Cytokine Responses and Is Required for Protective T Cell-Mediated Immunity against Trypanosoma cruzi Infection

• Published in: The Journal of immunology (1950) 2005-05, Vol.174 (10), p.6314-6321
• Main Authors: Silva, Elisabeth M, Guillermo, Landi V. C, Ribeiro-Gomes, Flavia L, De Meis, Juliana, Pereira, Renata M. S, Wu, Zhengqi, Calegari-Silva, Teresa C, Seabra, Sergio H, Lopes, Ulisses G, Siegel, Richard M, DosReis, George A, Lopes, Marcela F
• Format: Article
• Language: English
• Subjects: Animals; Caspase 8; Caspase Inhibitors; Caspases - biosynthesis; Caspases - physiology; Cell Differentiation - genetics; Cell Differentiation - immunology; Cells, Cultured; Chagas Disease - enzymology; Chagas Disease - genetics; Chagas Disease - immunology; Cytokines - biosynthesis; Cytokines - metabolism; Genetic Predisposition to Disease; Immunity, Cellular - genetics; Immunity, Innate - genetics; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Oligopeptides - pharmacology; Th2 Cells - cytology; Th2 Cells - enzymology; Th2 Cells - immunology; Th2 Cells - metabolism; Trypanosoma cruzi; Trypanosoma cruzi - immunology; Up-Regulation - genetics; Up-Regulation - immunology; Viral Proteins - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.10.6314

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.