Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 95, Issue 2, Pages 347-355Publisher
WILEY
DOI: 10.1189/jlb.0912463
Keywords
apoptosis; CD4 T cells; FasL; FLIP; cytokines
Categories
Funding
- United Nations Children's Fund (UNICEF)/United Nations Development Programme (UNDP)/World Bank/World Health Organization (WHO) Special Program for Research and Training in Tropical Diseases (TDR) [A60281]
- Howard Hughes Medical Institute [55003669]
- Brazilian National Research Council (CNPq)
- Rio de Janeiro State Science Foundation (Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro
- FAPERJ)
- National Institutes of Science and Technology-Instituto Nacional para Pesquisa Translacional em Saude e Ambiente na Regiao Amazonica (INCT-INPeTAm)/CNPq/Ministerio da Ciencia e Tecnologia (MCT)
- CNPq
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T cell expression of caspase-8 inhibitor vFLIP provides a Th1 cytokine environment, along with a protective Th2 response that increases 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- 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.
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