Clone tracking through repeated malaria identifies high-fidelity memory CD4 T cell responses
Jason Nideffera b, Florian A. Bacha, Felistas Nankyac, Kenneth Musinguzic, Šimon Bornab, Michelle Mantillab, Maato Zedic, Aracely Garcia Romeroa, Chloe Gerungana, Nora Yanga, Soyeon Kima, Kattria van der Ploega, Kylie Camanaga, Luis Lopeza, Evelyn Nansubugac, Joaniter Immaculate Nankabirwac, Emmanuel Arinaitwec, Potchara Boonrata, Steven Strubbeb, Alma‐Martina Cepikab, Saki Takahashid, Grant Dorseye, Bryan Greenhousee, Isabel Rodríguez-Barraquere f, Moses Robert Kamyac g, Rosa Bacchettab, Isaac Ssewanyanac, Ashraful Haqueh, Maria Grazia Roncarolob✉, Prasanna Jagannathana i✉
- aDepartment of Medicine, Stanford University, Stanford, CA, USA
- bDivision of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, USA
- cInfectious Diseases Research Collaboration, Kampala, Uganda
- dDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- eDepartment of Medicine, Division of HIV, ID, and Global Medicine, University of California San Francisco, San Francisco, CA, USA
- fChan Zuckerberg Biohub, San Francisco, CA, USA
- gDepartment of Medicine, Makerere University, Kampala, Uganda
- hDepartment of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia
- iDepartment of Microbiology and Immunology, Stanford University, Stanford, CA, USA
- ✉Corresponding author
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Abstract
Few studies have tracked human CD4 + 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 + T cell clonotypes during repeated Plasmodium falciparum ( Pf ) infections in Ugandan children and adults. Nearly all clonotypes displayed a strong preference for one of seven CD4 + 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 R 1) cells accounted for nearly 90% of Pf -specific CD4 + T cells in blood. Tracking these clones longitudinally for hundreds of days, we observed malaria-induced expansion of T R 1 effectors, long-term persistence of T R 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 R 1 cells.
TL;DRThis work establishes clonal fidelity as a natural phenomenon and demonstrates the stable, long-term memory potential of Tr1 cells. (Semantic Scholar)