Abstract
SummaryT 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.
Highlights
The generation of high-affinity antibodies requires naive CD4+ T cells to sequentially be activated, proliferate and differentiate, acquire proximity to the B cell follicles, and provide B cells with ‘‘help’’ in the form of antigen-specific interactions, co-receptor binding, and cytokine signaling
Further ICOSL stimulation from B cells is required for the final differentiation and maintenance of germinal center (GC)-T follicular helper (Tfh) cells (Pepper et al, 2011; Crotty, 2014), and this is consistent with studies showing that Inducible T cell co-stimulator (ICOS) is able to influence homing to GCs through the induction of filopodia (Franko and Levine, 2009; Xu et al, 2013)
(legend continued on page) noted that these mice accumulate a large population of Tfh cells, form GCs, and produce circulating, anti-DNA antibodies, and we proposed that the phosphoinositide-3 kinase (PI3K)-AKT-FOXO1 signaling pathway controls lineage commitment that, in part, specifies the Treg versus Tfh alternative cell fates (Kerdiles et al, 2010; Hedrick et al, 2012)
Summary
The generation of high-affinity antibodies requires naive CD4+ T cells to sequentially be activated, proliferate and differentiate, acquire proximity to the B cell follicles, and provide B cells with ‘‘help’’ in the form of antigen-specific interactions, co-receptor binding, and cytokine signaling. These specialized CD4 cells have been termed T follicular helper (Tfh) cells, and they are essential to promote the germinal center (GC) reaction including B cell expansion, class switching, selection, and development of high-affinity antibody-forming cells (Liu et al, 2013; Crotty, 2014; Ueno et al, 2015). In a manner not yet understood, this leads to increased expression of BCL6, which has been described as an essential transcription factor for the differentiation and function of Tfh cells (Choi et al, 2013)
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