ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells

• Published in: bioRxiv
• Main Authors: Panneton, Vincent, Mindt, Barbara C, Bouklouch, Yasser, Bouchard, Antoine, Saba Mohammaei, Chang, Jinsam, Witalis, Mariko, Li, Joanna, Stancescu, Albert, Bradley, John E, Randall, Troy D, Fritz, Jörg H, Woong-Kyung Suh
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 08.07.2022
• Subjects: Antibodies; Bcl-6 protein; Cell differentiation; CXCR5 protein; Flow cytometry; Foxp3 protein; Humoral immunity; Immunization; Immunological tolerance; Krueppel-like factor; Lymphocytes B; Lymphocytes T; NF-AT protein; Transcriptomes
• DOI: 10.1101/2021.09.14.460384

ICOS is a T cell costimulatory receptor critical for Tfh cell generation and function. However, the role of ICOS in Tfr cell differentiation remains unclear. Using Foxp3-Cre- mediated ICOS knockout (ICOS FC) mice, we show that ICOS deficiency in Treg-lineage cells drastically reduces the number of Tfr cells during GC reactions but has a minimal impact on conventional Treg cells. Single-cell transcriptome analysis of Foxp3+ cells at an early stage of the GC reaction suggests that ICOS normally inhibits Klf2 expression to promote follicular features including Bcl6 upregulation. Further, ICOS costimulation promotes nuclear localization of NFAT2, a known driver of CXCR5 expression. Notably, ICOS FC mice had an unaltered overall GC B cell output but showed signs of expanded autoreactive B cells along with elevated autoantibody titers. Thus, our study demonstrates that ICOS costimulation is critical for Tfr cell differentiation and highlights the importance of Tfr cells in maintaining humoral immune tolerance during GC reactions. Competing Interest Statement The authors have declared no competing interest. Footnotes * Figures 6 and 7 were removed to make the overall project more cohesive. Supplementary figure 2 was modified. Text was changed to fit the updated figures.