Clone tracking through repeated malaria identifies high-fidelity memory CD4 T cell responses
Few studies have tracked human CD4<sup>+</sup> T cell clones through repeated infections. We used longitudinal single-cell RNA and T cell receptor (TCR) tracking to study the functional stability and memory potential of CD4<sup>+</sup> T cell clonotypes during repeated <i>Plasmodium falciparum</i> (<i>Pf</i>) infections in Ugandan children and adults. Nearly all clonotypes displayed a strong preference for one of seven CD4<sup>+</sup> subsets. This phenomenon of "clonal fidelity" was influenced by clonal expansion, linking T cell polarization and proliferation in vivo. Using clone tracking, we characterized subset-specific activation trajectories and identified antigen-specific clones. Type 1 regulatory T (T<sub>R</sub>1) cells accounted for nearly 90% of <i>Pf</i>-specific CD4<sup>+</sup> T cells in blood. Tracking these clones longitudinally for hundreds of days, we observed malaria-induced expansion of T<sub>R</sub>1 effectors, long-term persistence of T<sub>R</sub>1 memory cells, and high-fidelity recall responses after reinfection. This work establishes clonal fidelity as a natural phenomenon and demonstrates the stable, long-term memory potential of T<sub>R</sub>1 cells.
Authors
- Maria Grazia Roncarolo (ORCID: https://orcid.org/0000-0003-1636-1495)
- Chloe Gerungan
- Šimon Borna (ORCID: https://orcid.org/0000-0001-8445-2634)
- Jason Nideffer (ORCID: https://orcid.org/0000-0002-4421-8656)
- Isaac Ssewanyana
- Prasanna Jagannathan (ORCID: https://orcid.org/0000-0001-6305-758X)
- Kattria van der Ploeg (ORCID: https://orcid.org/0000-0002-3183-3190)
- Grant Dorsey (ORCID: https://orcid.org/0000-0003-0740-0317)
- Saki Takahashi (ORCID: https://orcid.org/0000-0001-5413-5507)
- Alma‐Martina Cepika (ORCID: https://orcid.org/0000-0003-2862-1901)
- Florian A. Bach (ORCID: https://orcid.org/0000-0002-0126-5516)
- Isabel Rodríguez-Barraquer (ORCID: https://orcid.org/0000-0001-6784-1021)
- Joaniter I. Nankabirwa (ORCID: https://orcid.org/0000-0001-7818-3845)
- Ashraful Haque (ORCID: https://orcid.org/0000-0003-2260-0026)
- Bryan Greenhouse (ORCID: https://orcid.org/0000-0003-0287-9111)
- Felistas Nankya
- Michelle Mantilla
- Maato Zedi (ORCID: https://orcid.org/0000-0001-9430-0626)
- Steven Strubbe (ORCID: https://orcid.org/0000-0003-0361-2523)
- Rosa Bacchetta (ORCID: https://orcid.org/0000-0002-0606-6268)
- Kenneth Musinguzi (ORCID: https://orcid.org/0000-0001-6890-8988)
- Moses Robert Kamya (ORCID: https://orcid.org/0000-0001-9106-4234)
- Potchara Boonrat
- Soyeon Kim (ORCID: https://orcid.org/0000-0003-1573-2733)
- Luis López (ORCID: https://orcid.org/0009-0000-2227-6524)
- Emmanuel Arinaitwe
- Kylie Camanag
- Nora Yang
- Asunción Romero (ORCID: https://orcid.org/0000-0002-7845-1296)
- Evelyn Nansubuga
Institutions
- Johns Hopkins University (US)
- The University of Melbourne (AU)
- University of California, San Francisco (US)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Peter Doherty Institute (AU)
- Infectious Diseases Research Collaboration (UG)
- Chan Zuckerberg Initiative (United States) (US)
- Stanford Medicine (US)
- Makerere University (UG)
- University of San Francisco (US)
- Stanford University (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-04-25
- DOI
- https://doi.org/10.1126/sciimmunol.ads2957
- Citations
- 5
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 3.99