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. 2023 Feb 3;14:1125503. doi: 10.3389/fimmu.2023.1125503

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Copyright © 2023 Betzler, Ushmorov and Brunner

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) and the copyright owner(s) 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.

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Transcriptional control of Tfr cell differentiation. Initial Tfr cell differentiation depends on CD28 and ICOS signaling, whereas interaction with B cells via SLAM/SAP is required for their full differentiation. Tfr cells express both BCL-6 and BLIMP-1 and possibly their balanced regulation is essential for Tfr cell differentiation. BCL-6 is regulated by ICOS and mTORC1. ICOS induces PI3K and its subunit p85α interacts with osteopontin (OPN-i). OPN-i translocates to the nucleus preventing BCL-6 from ubiquitin-dependent proteasome degradation. mTORC1 induces phosphorylation of STAT3, activating TCF-1 expression, which upregulates BCL-6. Stromal interacting molecules (STIM) and ORAI proteins mediate Ca2+ entry inducing NFAT2, which upregulates CXCR5. Id2/Id3, c-Maf and BOB.1/OBF.1 are also involved in Tfr cell differentiation, but the exact mechanisms are incompletely understood so far. This figure was created with BioRender.com.