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Imaging effector functions of human cytotoxic CD4+ T cells specific for Plasmodium falciparum circumsporozoite protein
Authors:Frevert Ute  Moreno Alberto  Calvo-Calle J Mauricio  Klotz Christian  Nardin Elizabeth
Institution:Department of Medical Parasitology, New York University School of Medicine, 341 E 25 St, New York, NY 10010, USA
Abstract:Malaria vaccines, comprised of irradiated Plasmodium falciparum sporozoites or a synthetic peptide containing T and B cell epitopes of the circumsporozoite protein (CSP), elicit multifunctional cytotoxic and non-cytotoxic CD4+ T cells in immunised volunteers. Both lytic and non-lytic CD4+T cell clones recognised a series of overlapping epitopes within a ‘universal’ T cell epitope EYLNKIQNSLSTEWSPCSVT of CSP (NF54 isolate) that was presented in the context of multiple DR molecules. Lytic activity directly correlated with T cell receptor (TCR) functional avidity as measured by stimulation indices and recognition of naturally occurring variant peptides. CD4+ T cell-mediated cytotoxicity was contact-dependent and did not require de novo synthesis of cytotoxic mediators, suggesting a granule-mediated mechanism. Live cell imaging of the interaction of effector and target cells demonstrated that CD4+ cytotoxic T cells recognise target cells with their leading edge, reorient their cytotoxic granules towards the zone of contact, and form a stable immunological synapse. CTL attacks induced chromatin condensation, nuclear fragmentation and formation of apoptotic bodies in target cells. Together, these findings suggest that CD4+ CTLs trigger target cell apoptosis via classical perforin/granzyme-mediated cytotoxicity, similar to CD8+ CTLs, and these multifunctional sporozoite- and peptide-induced CD4+ T cells have the potential to play a direct role as effector cells in targeting the exoerythrocytic forms within the liver.
Keywords:Malaria  Vaccine  CTL  Perforin  Granzymes  Apoptosis  Immunological synapse  Cytotoxic granule  Live cell imaging
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