Single-cell RNA-sequencing on human naïve and memory CD4+ T cells during Plasmodium falciparum infection

ABSTRACT: Plasmodium falciparum (Pf) malaria causes high rates of morbidity and mortality and lacks an effective vaccine. Clinical immunity develops in residents of malaria endemic regions which confers reduced clinical symptoms during infection and protects against severe disease. We hypothesized that understanding the immune mechanisms of clinical immunity could inform vaccine design to improve efficacy. We compared the peripheral blood cellular and humoral immune responses during Pf malaria infection between clinically susceptible and protected participants from a malaria endemic region in Malawi during a prospective 18-month longitudinal study. Participant classifications were defined by the number of recurrent clinical malaria episodes with susceptible participants having more than three while protected less than one episode during the study period. Protected participants exhibited higher immunoglobulin G (IgG) breadth and titers against Pf antigens, and greater antibody (Ab)-dependent Pf opsonization compared to susceptible participants, consistent with our classifications. Using high dimensional mass cytometry (CyTOF) and spectral flow cytometry, and single-cell transcriptomic analyses, we identified expanded memory CD4+ T cell clonotypes in the blood of protected participants undergoing malaria infection. These cells express a strong cytolytic T helper 1 effector program with transcripts encoding granzymes (A, B, H, M), granulysin, NKG7 and the ZEB2 master transcriptional regulator of terminally differentiated effector T cells. ZEB2+ memory CD4+ T cells were CD39hiTIGIThi and expressed multiple chemotactic and inhibitory receptors. Yet, their levels of several chemokine and checkpoint inhibitory receptors were reduced in protected compared to susceptible individuals. We propose that clonally expanded ZEB2+ cytolytic memory CD4+ Th1 cells could represent essential contributors to clinical immunity against Pf malaria infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182536 | GEO | 2021/08/28

REPOSITORIES: GEO