Imaging effector functions of human cytotoxic CD4+ T cells specific for Plasmodium falciparum circumsporozoite protein.
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.
Frevert
Ute
U
Department of Medical Parasitology, New York University School of Medicine, 341 E 25 St, New York, NY 10010, USA.
Moreno
Alberto
A
Calvo-Calle
J Mauricio
JM
Klotz
Christian
C
Nardin
Elizabeth
E
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D054992:Immunological Synapses; D016778:Malaria, Falciparum / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D034101:Sporozoites / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000953:Antigens, Protozoan; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015800:Protozoan Proteins; D011948:Receptors, Antigen, T-Cell; C041595:circumsporozoite protein, Protozoan