TCR clonotyping of paired blood and tonsillar T-follicular cells reveals the mixed origin of CD38high Tfrs
6 affiliations
- 1Institute of Translational Medicine, Pirogov Russian National Research Medical University
- 2Center for Bio and Medical Technology
- 3Genomics of Adaptive Immunity Department, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry
- 4Department of Otholaryngology, Pirogov Russian National Research Medical University
- 5Department of Otholaryngology, City Clinical Hospital No. 1 named after N.I. Pirogov
- 6Sverzhevsky Scientific Research Clinical Institute of Otorhinolaryngology
Abstract
Circulating T follicular regulatory (cTfr) cells are measured as blood biomarkers after vaccination, in autoimmune disease (e.g., lupus, rheumatoid arthritis) and cancer immunotherapy, yet whether they originate from natural Tregs (yielding nTfr) or germinal center T follicular helper (GC Tfh) cells (yielding iTfr) remains unknown. This distinction is critical for interpreting cTfr expansion as Treg-derived regulation versus Tfh-derived negative feedback. To characterize tonsillar follicular T cell heterogeneity and resolve the origins of cTfr cells we applied single-cell multiomics and bulk T cell receptor sequencing (TCRβ-seq) analysis of matched human tonsil and blood. Tonsillar nTfr and iTfr cells distribute across shared transcriptional states, with CD38 expression distinguishing iTfr from nTfr in most contexts. However, within a transitional cluster positioned between activated Tfh and Tfr cells, nTfr-like cells also upregulated CD38, indicating that its specificity for iTfr is not absolute. Peripheral blood CD38 ⁻ cTfr cells shared clonotypes exclusively with non-follicular Tregs and lacked overlap with GC Tfh, indicating predominantly Treg origin. CD38 high cTfr cells captured a mixed population: some shared clonotypes with tonsillar GC Tfh (iTfr), while others shared clonotypes with non-follicular Tregs (nTfr). These findings establish that accurate discrimination of iTfr versus nTfr within the CD38 high compartment requires TCR clonal reference to matched tissue.
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BibTeX
@article{sokolova2026clonotyping,
title = {{TCR clonotyping of paired blood and tonsillar T-follicular cells reveals the mixed origin of CD38high Tfrs}},
author = {Sophiya R. Sokolova and Vladimir A. Grigoriants and Irina A. Shagina and Ekaterina V. Barsova and Maria A. Nomerovskaya and Jamilya Z. Khalifaeva and Alexander V. Gurov and Olga V. Britanova and Ivan V. Zvyagin and Dmitriy M. Chudakov and Irina L. Grigorova},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1947623},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1947623/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - TCR clonotyping of paired blood and tonsillar T-follicular cells reveals the mixed origin of CD38high Tfrs
AU - Sophiya R. Sokolova
AU - Vladimir A. Grigoriants
AU - Irina A. Shagina
AU - Ekaterina V. Barsova
AU - Maria A. Nomerovskaya
AU - Jamilya Z. Khalifaeva
AU - Alexander V. Gurov
AU - Olga V. Britanova
AU - Ivan V. Zvyagin
AU - Dmitriy M. Chudakov
AU - Irina L. Grigorova
PY - 2026
DA - 2026/10/09
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1947623
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1947623/full
AB - Circulating T follicular regulatory (cTfr) cells are measured as blood biomarkers after vaccination, in autoimmune disease (e.g., lupus, rheumatoid arthritis) and cancer immunotherapy, yet whether they originate from natural Tregs (yielding nTfr) or germinal center T follicular helper (GC Tfh) cells (yielding iTfr) remains unknown. This distinction is critical for interpreting cTfr expansion as Treg-derived regulation versus Tfh-derived negative feedback. To characterize tonsillar follicular T cell heterogeneity and resolve the origins of cTfr cells we applied single-cell multiomics and bulk T cell receptor sequencing (TCRβ-seq) analysis of matched human tonsil and blood. Tonsillar nTfr and iTfr cells distribute across shared transcriptional states, with CD38 expression distinguishing iTfr from nTfr in most contexts. However, within a transitional cluster positioned between activated Tfh and Tfr cells, nTfr-like cells also upregulated CD38, indicating that its specificity for iTfr is not absolute. Peripheral blood CD38 ⁻ cTfr cells shared clonotypes exclusively with non-follicular Tregs and lacked overlap with GC Tfh, indicating predominantly Treg origin. CD38 high cTfr cells captured a mixed population: some shared clonotypes with tonsillar GC Tfh (iTfr), while others shared clonotypes with non-follicular Tregs (nTfr). These findings establish that accurate discrimination of iTfr versus nTfr within the CD38 high compartment requires TCR clonal reference to matched tissue.
SN - 1664-3224
ER -