Longitudinal T cell receptor repertoire sequencing identifies specific T cell clones with rare CDR3 residues against malaria 2306928

Abstract Introduction Naturally acquired immunity (NAI) against malaria develops gradually with age and wanes in the absence of continuous antigen exposure. Comparative analysis of T cell receptor (TCR) repertoires provides valuable insight into T cell development and immune responses during infection. Methods In this study, we analyzed longitudinal TCRb repertoire data from a well-characterized cohort of Malian young children with malaria and established a statistical framework to identify TCRb clone proliferation and contraction over time. Results We detected hundreds of malaria-responsive TCRbs per individual, encompassing both memory-like and newly emerged clones. Although these responding TCRs were largely private, analysis of the complementarity-determining region 3 (CDR3) antigen-contacting FG loop revealed distinct amino acid doublet usage patterns. Malaria expanded CD4+ TCRbs preferentially utilized rare residue doublets such as SW and AM, whereas CD8+ TCRbs promoted DV, FQ, RW, and SI doublets. Conclusion As memory T cell responses depend on effective antigen presentation, our approach provides new mechanistic insights into the development of NAI against malaria and offers a potential framework to inform vaccine design. Funding Source NIH intramural research funding Topic Categories Immune Mechanisms of Human Disease (HUM)