AUTHOR=Heide Janna , Wildner Nils H. , Ackermann Christin , Wittner Melanie , Marget Matthias , Sette Alessandro , Sidney John , Jacobs Thomas , Schulze zur Wiesch Julian 

TITLE=Detection of EXP1-Specific CD4+ T Cell Responses Directed Against a Broad Range of Epitopes Including Two Promiscuous MHC Class II Binders During Acute Plasmodium falciparum Malaria

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.03037

DOI=10.3389/fimmu.2019.03037

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</bold> T cells are thought to play a major role in conferring immunity against malaria. This study aimed to comprehensively define the breadth and specificity of the <italic>Plasmodium falciparum (P. falciparum)</italic>-specific CD4+ T cell response directed against the exported protein 1 (EXP1) in a cohort of patients diagnosed with acute malaria.</p><p><bold>Methods:</bold> Peripheral blood mononuclear cells of 44 patients acutely infected with <italic>P. falciparum</italic>, and of one patient infected with <italic>P. vivax</italic>, were stimulated and cultured <italic>in vitro</italic> with an overlapping set of 31 <italic>P. falciparum</italic>-specific 13-17-mer peptides covering the entire EXP1 sequence. EXP1-specific T cell responses were analyzed by ELISPOT and intracellular cytokine staining for interferon-γ production after re-stimulation with individual peptides. For further characterization of the epitopes, <italic>in silico</italic> and <italic>in vitro</italic> human leukocyte antigen (HLA) binding studies and fine mapping assays were performed.</p><p><bold>Results:</bold> We detected one or more EXP1-specific CD4+ T cell responses (mean: 1.09, range 0–5) in 47% (21/45) of our patients. Responses were directed against 15 of the 31 EXP1 peptides. Peptides EXP1-P13 (aa60-74) and P15 (aa70-85) were detected by 18% (<italic>n</italic> = 8) and 27% (<italic>n</italic> = 12) of the 45 patients screened. The optimal length, as well as the corresponding most likely HLA-restriction, of each of these two peptides was assessed. Interestingly, we also identified one CD4+ T cell response against peptide EXP1-P15 in a patient who was infected with <italic>P. vivax</italic> but not <italic>falciparum</italic>.</p><p><bold>Conclusions:</bold> This first detailed characterization of novel EXP1-specific T cell epitopes provides important information for future analysis with major histocompatibility complex-multimer technology as well as for immunomonitoring and vaccine design.</p>