T follicular helper (Tfh) cells are essential for the development of germinal center B cells and high-affinity antibody-producing B cells in humans and mice. Here, we identify the guanine nucleotide exchange factor (GEF) Rin-like (Rinl) as a negative regulator of Tfh generation. Loss of Rinl leads to an increase of Tfh in aging, upon in vivo immunization and acute LCMV Armstrong infection in mice, and in human CD4+ T cell in vitro cultures. Mechanistically, adoptive transfer experiments using WT and Rinl-KO naïve CD4+ T cells unraveled T cell–intrinsic GEF-dependent functions of Rinl. Further, Rinl regulates CD28 internalization and signaling, thereby shaping CD4+ T cell activation and differentiation. Thus, our results identify the GEF Rinl as a negative regulator of global Tfh differentiation in an immunological context and species-independent manner, and furthermore, connect Rinl with CD28 internalization and signaling pathways in CD4+ T cells, demonstrating for the first time the importance of endocytic processes for Tfh differentiation.
The guanine nucleotide exchange factor Rin-like controls Tfh cell differentiation via CD28 signaling
Disclosures: M. Iannacone consults or sits on advisory boards for the following companies: Asher Biotherapeutics, San Carlos, CA; GentiBio, Cambridge, MA; Clexio Biosciences, Petach Tikva, Israel; Sybilla Biotech, Trento, Italy; BlueJay Therapeutics, San Mateo, CA; Bristol Myers Squibb, New York, NY; and Aligos Therapeutics, South San Francisco, CA. No other disclosures were reported.
- Award Id(s): P19223,F7005,P27747,P24265,P30885,F7004,doc.funds (DOC) Programme 32
- Award Id(s): PRIN-2017ZXT5WR,PRIN-20209Y5YFZ
Lisa Sandner, Marlis Alteneder, Ramona Rica, Barbara Woller, Eleonora Sala, Tobias Frey, Anela Tosevska, Ci Zhu, Moritz Madern, Matarr Khan, Pol Hoffmann, Alexandra Schebesta, Ichiro Taniuchi, Michael Bonelli, Klaus Schmetterer, Matteo Iannacone, Mirela Kuka, Wilfried Ellmeier, Shinya Sakaguchi, Ruth Herbst, Nicole Boucheron; The guanine nucleotide exchange factor Rin-like controls Tfh cell differentiation via CD28 signaling. J Exp Med 6 November 2023; 220 (11): e20221466. doi: https://doi.org/10.1084/jem.20221466
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