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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Immunological Tolerance and Regulation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1519780

BLIMP-1-dependent differentiation of T Follicular Helper cells into Foxp3+ T regulatory type 1 cells

Provisionally accepted
Pere Santamaria Pere Santamaria 1*Josep Garnica Josep Garnica 2Jun Yamanouchi Jun Yamanouchi 1Robert Clarke Robert Clarke 1Joel Moro Joel Moro 2Shari Thiessen Shari Thiessen 1Javier Montaño Sierra Javier Montaño Sierra 2Debajyoti Mondal Debajyoti Mondal 1Pau Serra Devecchi Pau Serra Devecchi 2
  • 1 University of Calgary, Calgary, Canada
  • 2 August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Catalonia, Spain

The final, formatted version of the article will be published soon.

    T-regulatory-type-1 (TR1) cells are a subset of interleukin-10-producing but Foxp3-Treg cells that arise in response to chronic antigenic stimulation. We have shown that systemic delivery of autoimmune disease-relevant peptide-major histocompatibility complex class II (pMHCII)-coated nanoparticles (pMHCII-NP) triggers the formation of large pools of disease-suppressing Foxp3-TR1 cells from cognate T-follicular helper (TFH) cell precursors. Here we show that, upon treatment withdrawal, these Foxp3-TR1 cells spontaneously differentiate into a novel immunoregulatory Foxp3+ TR1 subset that inherits epigenetic and transcriptional hallmarks of their precursors, including clonotypic T-cell receptors, and is distinct from other Foxp3+ Treg subsets. Whereas the transcription factor BLIMP-1 is dispensable for development of conventional Foxp3+ Treg cells, it is necessary for development of Foxp3+ TR1 cells. In a model of central nervous system autoimmunity, abrogation of BLIMP-1 or IL-10 expression in the Foxp3-and/or Foxp3+ TR1 subsets inhibits their development or anti-encephalitogenic activity. Thus, the TFH-TR1 transdifferentiation pathway results in the generation of two distinct autoimmune diseasesuppressing, IL-10-producing TR1 subsets that are distinguished by the expression of Foxp3 and Foxp3 target genes.

    Keywords: peptide-major histocompatibility complex (pMHC), Nanomedicine, T-follicular helper cells, T-Regulatory Type-1 cells, Foxp3+ T-Regulatory Type-1 cells, BLIMP-1

    Received: 30 Oct 2024; Accepted: 27 Jan 2025.

    Copyright: © 2025 Santamaria, Garnica, Yamanouchi, Clarke, Moro, Thiessen, Montaño Sierra, Mondal and Serra Devecchi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Pere Santamaria, University of Calgary, Calgary, Canada

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