Clone tracking through repeated malaria identifies high-fidelity memory CD4 T cell responses.

Area of Science:

• Immunology
• Infectious Diseases
• Cellular Biology

Background:

• Understanding T cell responses during repeated infections is crucial for vaccine development.
• Few studies have longitudinally tracked human CD4+ T cell clones through multiple infection cycles.
• The stability and memory potential of specific CD4+ T cell subsets remain incompletely understood.

Purpose of the Study:

• To investigate the functional stability and memory potential of CD4+ T cell clonotypes during repeated Plasmodium falciparum infections.
• To characterize subset-specific activation trajectories and identify antigen-specific clones.
• To establish clonal fidelity as a natural phenomenon and assess the long-term memory of Type 1 regulatory T cells.

Main Methods:

• Longitudinal single-cell RNA sequencing and T cell receptor (TCR) tracking.
• Analysis of CD4+ T cell clonotypes in Ugandan children and adults during repeated malaria infections.
• Tracking of antigen-specific T cell clones over hundreds of days.

Main Results:

• Nearly all CD4+ T cell clonotypes exhibited strong fidelity to one of seven CD4+ subsets.
• Type 1 regulatory T (Treg1) cells constituted nearly 90% of Plasmodium falciparum-specific CD4+ T cells.
• Observed malaria-induced expansion of Treg1 effectors, long-term persistence of Treg1 memory cells, and high-fidelity recall responses post-reinfection.

Conclusions:

• Clonal fidelity is a natural phenomenon in human CD4+ T cell responses.
• Type 1 regulatory T cells possess stable, long-term memory potential following malaria infection.
• This study provides insights into the cellular mechanisms underlying sustained immunity to Plasmodium falciparum.