The role of plasmodium-specific cytolytic CD4+ t cells in malaria immunity

The National Institute of Allergy and Infectious Diseases awarded Albert Einstein College of Medicine a project grant of $100,228 on December 4, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to support research on the role of Plasmodium-specific cytolytic CD4+ T cells in malaria immunity.

The research defines epitope specificity of expanded T cell clones from clinically immune individuals, characterizes the phenotype and function of ZEB2+ CD4+ T cells upon Plasmodium falciparum restimulation using banked peripheral blood mononuclear cell samples, and investigates the kinetics, differentiation, function, and protective capacity of cytolytic ZEB2+ CD4+ T cells during malaria infection using murine models of radiation attenuated sporozoite immunization and live sporozoite challenge. The project aims to identify T cell-mediated mechanisms of malaria immunity to inform development of more effective, T cell-based malaria interventions and vaccines. The fellowship provides comprehensive training in translational immunology, high-dimensional immune profiling, T cell biology, and murine models of infection, including formal coursework, scientific communication, and career mentoring.

Place of performance is Bronx, New York. The period of performance runs through June 30, 2029.

Abstract

Malaria, caused by plasmodium falciparum (PF) remains a major human parasitic disease responsible for over half a million deaths each year. In endemic regions, individuals gradually acquire non-sterilizing, non-durable clinical immunity to plasmodium falciparum (PF), but the cellular mechanisms underlying this protection remain poorly defined. The long-term objective of this research is to identify t cell-mediated mechanisms of malaria immunity to inform the development of more effective, t cell-based malaria interventions and vaccines. Recent immune profiling of a longitudinal cohort in a malaria endemic region in malawi identified a clonally expanded population of cytolytic ZEB2+ CD4+ t cells in the blood of PF-infected participants, which react to the PF liver-stage circumsporozoite (CSP) antigen and express a robust cytotoxic gene signature, suggesting a potential role in limiting liver-stage parasitic infection. The proposed research will (1) define the epitope specificity of expanded t cell clones from clinically immune individuals, (2) characterize the phenotype and function of ZEB2+ CD4+ t cells upon PF restimulation using banked peripheral blood mononuclear cell (pbmc) samples, and (3) use murine models of radiation attenuated sporozoite (RAS) immunization and live sporozoite challenge to investigate the kinetics, differentiation, function, and protective capacity of cytolytic ZEB2+ CD4+ t cells during malaria infection. This F31 fellowship will provide comprehensive training in translational immunology, high-dimensional immune profiling, t cell biology, and murine models of infection. The training plan includes formal coursework, scientific communication, and career mentoring. Research will be conducted in a collaborative, multidisciplinary environment that combines expertise in t cell biology, malaria pathogenesis, and clinical research. The sponsor and cosponsor have a strong track record of CO-mentorship and a demonstrated commitment to trainee development, ensuring a supporting and rigorous setting for most optimal predoctoral training.