(226) Longitudinal T cell receptor repertoire sequencing identifies specific T cell clones with rare CDR3 residues against malaria

Introduction/Rationale: 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.