ICOS Coreceptor Signaling Inactivates the Transcription Factor FOXO1 to Promote Tfh Cell Differentiation

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2015 Feb 19

PMID 25692700

Citations 140

Authors

Erica L Stone

Marion Pepper

Carol D Katayama

Yann M Kerdiles

Chen-Yen Lai

Elizabeth Emslie

Yin C Lin

Edward Yang

Ananda W Goldrath

Ming O Li

Doreen A Cantrell

Stephen M Hedrick

Affiliations

Soon will be listed here.

Abstract

T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1(-/-) GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner.

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