Critical roles of ICOS in controlling Foxp3-expressing T follicular cell subsets during early-stage germinal center reactions

BioRxiv : the Preprint Server for Biology
V. PannetonWoong-Kyung Suh

Abstract

The inducible costimulator (ICOS) is a T cell costimulatory receptor critical for humoral immunity. In mice and humans, ICOS deficiency leads to a lack of T follicular helper (Tfh) cells and protective antibodies. However, the role of ICOS in T follicular regulatory (Tfr) cell generation and function remains poorly understood. Using Foxp3-cre-mediated ICOS knockout (ICOS FC) mice, we show that T regulatory (Treg)-specific ICOS deletion drastically reduces the number of Tfr cells without altering Treg cell numbers. Further, we observed a lowered ratio of antigen-specific germinal center B (GC B) cells and increased anti-nuclear antibodies in ICOS FC mice, suggesting a rise of autoreactive GC B cells. Single-cell transcriptome analysis revealed shifts in transitory Tfr precursor populations in immunized ICOS FC mice. Mechanistically, our data suggest that ICOS promotes the Treg-to-Tfr transition by regulating KLF2 and NFAT2 with downstream impacts on Bcl6 and CXCR5 expression. Importantly, we discovered a Tfr subset originating from Foxp3- precursors by analyzing flow cytometry data of immunized mice in which ICOS expression in Foxp3+ cells was ablated at different stages of GC reactions. Consistently, single-cell transcriptome a...Continue Reading

Methods Mentioned

BETA
PCA
Chip
flow cytometry
Flow cytometry gating
ELISA

Software Mentioned

Modularity Optimizer
Cellranger
Monocle3
Ensembl
R
R library
Seurat
ImageJ
PANTHER
R Seurat

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