Repertoire-based mapping and time-tracking of T helper cell subsets in scRNA-Seq

This approach accurately positions the Th1, Th1-17, Th17, Th22, Th2a, Th2, T follicular helper (Tfh), and regulatory T-cell (Treg) subsets, outperforming mapping based on CITE-Seq. Remarkably, the mapping is tightly focused on specific scRNA-Seq clusters, despite 4-year interval between subset sorting and the effector CD4+ scRNA-Seq experiment. These findings highlight the intrinsic program stability of Th clones circulating in peripheral blood. Repertoire overlap analysis at the scRNA-Seq level confirms that the circulating Th1, Th2, Th2a, Th17, Th22, and Treg subsets are clonally independent. However, a significant clonal overlap between the Th1 and cytotoxic CD4+ T-cell clusters suggests that cytotoxic CD4+ T cells differentiate from Th1 clones. In addition, this study resolves a longstanding ambiguity: we demonstrate that, while CCR10+ Th cells align with a specific Th22 scRNA-Seq cluster, CCR10-CCR6+CXCR3-CCR4+ cells, typically classified as Th17, represent a mixture of bona fide Th17 cells and clonally unrelated CCR10low Th22 cells. The clear distinction between the Th17 and Th22 subsets should influence the development of vaccine- and T-cell-based therapies. Furthermore, we show that severe acute SARS-CoV-2 infection induces systemic type 1 interferon (IFN) activation of naive Th cells. An increased proportion of effector IFN-induced Th cells is associated with a moderate course of the disease but remains low in critical COVID-19 cases. Using integrated scRNA-Seq, TCR-Track, and CITE-Seq data from 122 donors, we provide a comprehensive Th scRNA-Seq reference that should facilitate further investigation of Th subsets in fundamental and clinical studies.

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Lukyanov, D.K., Kriukova, V.V., Ladell, K., Shagina, I.A., Staroverov, D.B., Minasian, B.E., Fedosova, A.S., Shelyakin, P., Suchalko, O.N., Komkov, A.Y., Blagodatskikh, K.A., Miners, K.L., Britanova, O.V., Franke, A., Price, D.A., Chudakov, D.M., 2025. Repertoire-based mapping and time-tracking of T helper cell subsets in scRNA-Seq. Front. Immunol. 16, 1536302. https://doi.org/10.3389/fimmu.2025.1536302
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