Cytolytic circumsporozoite-specific memory CD4+ T cell clones are expanded during Plasmodium falciparum infection

Raquel Furtado, Mahinder Paul, Jinghang Zhang, Joowhan Sung, Paul Karell, Ryung S. Kim, Sophie Caillat-Zucman, Li Liang, Philip Felgner, Andy Bauleni, Syze Gama, Andrea Buchwald, Terrie Taylor, Karl Seydel, Miriam Laufer, Fabien Delahaye, Johanna P. Daily () and Grégoire Lauvau ()
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Raquel Furtado: Albert Einstein College of Medicine, Bronx
Mahinder Paul: Albert Einstein College of Medicine, Bronx
Jinghang Zhang: Albert Einstein College of Medicine, Bronx
Joowhan Sung: Albert Einstein College of Medicine, Bronx
Paul Karell: Albert Einstein College of Medicine, Bronx
Ryung S. Kim: Albert Einstein College of Medicine, Bronx
Sophie Caillat-Zucman: Université de Paris, AP-HP, Hôpital Saint-Louis, Laboratoire d’Immunologie et Histocompatiblité, INSERM UMR976
Li Liang: University of California
Philip Felgner: University of California
Andy Bauleni: Kamuzu University of Health Sciences
Syze Gama: Kamuzu University of Health Sciences
Andrea Buchwald: University of Maryland School of Medicine
Terrie Taylor: Kamuzu University of Health Sciences
Karl Seydel: Kamuzu University of Health Sciences
Miriam Laufer: University of Maryland School of Medicine
Fabien Delahaye: Albert Einstein College of Medicine, Bronx
Johanna P. Daily: Albert Einstein College of Medicine, Bronx
Grégoire Lauvau: Albert Einstein College of Medicine, Bronx

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Clinical immunity against Plasmodium falciparum infection develops in residents of malaria endemic regions, manifesting in reduced clinical symptoms during infection and in protection against severe disease but the mechanisms are not fully understood. Here, we compare the cellular and humoral immune response of clinically immune (0-1 episode over 18 months) and susceptible (at least 3 episodes) during a mild episode of Pf malaria infection in a malaria endemic region of Malawi, by analysing peripheral blood samples using high dimensional mass cytometry (CyTOF), spectral flow cytometry and single-cell transcriptomic analyses. In the clinically immune, we find increased proportions of circulating follicular helper T cells and classical monocytes, while the humoral immune response shows characteristic age-related differences in the protected. Presence of memory CD4+ T cell clones with a strong cytolytic ZEB2+ T helper 1 effector signature, sharing identical T cell receptor clonotypes and recognizing the Pf-derived circumsporozoite protein (CSP) antigen are found in the blood of the Pf-infected participants gaining protection. Moreover, in clinically protected participants, ZEB2+ memory CD4+ T cells express lower level of inhibitory and chemotactic receptors. We thus propose that clonally expanded ZEB2+ CSP-specific cytolytic memory CD4+ Th1 cells may contribute to clinical immunity against the sporozoite and liver-stage Pf malaria.

Date: 2023
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DOI: 10.1038/s41467-023-43376-y

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