Journal Article

DZNE-2026-00852

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png TGF-β and IL-2 differentially shape T follicular regulatory cell differentiation and stability in vitro.

Bach, L. ; Chang, Y. ; Arteaga Transito, O. ; Ghasemi, M. ; Steinheuer, L. M. ; Steffen, T. ; De Domenico, E.DZNE* ; Ulas, T.DZNE* ; Wunderlich, F. T. ; Beyer, M. D.DZNE* ; Thurley, K. ; Baumjohann, D.

2026
Nature Publ. Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41423-026-01440-9

Abstract: T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells play critical roles in regulating the activity of the germinal center (GC), which is essential for the generation of high-affinity antibodies. In the GC, Tfh cells help B cells to proliferate and to differentiate into memory B cells and long-lived plasma cells. In contrast, Tfr cells, a specialized subset of regulatory T cells (Tregs), modulate the humoral immune response by suppressing excessive or autoreactive B-cell activity. Here, we established an in vitro differentiation protocol for mouse CD4⁺ T cells that yielded CXCR5⁺FoxP3⁺ Tfr cells that exhibited a Bcl6hiPD-1hiCD25loGITRint phenotype and were distinct from Treg and Tfh cells. Functionally, in vitro-generated Tfr cells potently suppressed Tfh cell-driven B-cell class switching to IgG1 and downregulated the expression of B-cell costimulatory ligands. While in vitro-generated Bcl6-deficient Tfh cells were impaired in providing help to B cells for efficient class switching to IgG1, in vitro-generated Bcl6-deficient Tfr cells failed to inhibit Tfh cell-driven B-cell class switching to IgG1. Mechanistically, we showed that Tfr cells emerged from FoxP3+ precursors in low-IL-2 environments through a TGF-β- and c-Maf-dependent pathway, allowing for reprogramming and reinforcement of the follicular regulatory cell program in CD4+ T cells in vitro.

Keyword(s): Animals (MeSH) ; Cell Differentiation (MeSH) ; T-Lymphocytes, Regulatory: immunology (MeSH) ; T-Lymphocytes, Regulatory: cytology (MeSH) ; Interleukin-2: metabolism (MeSH) ; Transforming Growth Factor beta: metabolism (MeSH) ; Proto-Oncogene Proteins c-bcl-6: metabolism (MeSH) ; Proto-Oncogene Proteins c-bcl-6: genetics (MeSH) ; Germinal Center: immunology (MeSH) ; Mice (MeSH) ; B-Lymphocytes: immunology (MeSH) ; Receptors, CXCR5: metabolism (MeSH) ; Proto-Oncogene Proteins c-maf: metabolism (MeSH) ; T Follicular Helper Cells: immunology (MeSH) ; Forkhead Transcription Factors: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; T-Lymphocytes, Helper-Inducer: immunology (MeSH) ; Immunoglobulin Class Switching (MeSH) ; Immunoglobulin G (MeSH) ; Lymphocyte Activation (MeSH) ; CXCR5 ; FoxP3 ; IL-2 ; T follicular regulatory cells ; c-Maf ; Interleukin-2 ; Transforming Growth Factor beta ; Proto-Oncogene Proteins c-bcl-6 ; Receptors, CXCR5 ; Proto-Oncogene Proteins c-maf ; Forkhead Transcription Factors ; Bcl6 protein, mouse ; Immunoglobulin G

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Contributing Institute(s):

1. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
2. Immunogenomics and Neurodegeneration (AG Beyer)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
2. 351 - Brain Function (POF4-351) (POF4-351)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Essential Science Indicators ; IF >= 20 ; JCR ; Nationallizenz ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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