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

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.

Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis

“…Furthermore, FoxO1 positively controls Foxp3 gene expression and maintains the proper functioning of Tregs to suppress autoimmunity (48,53). It has been shown that FoxO1 is a negative regulator of Th17 by inhibiting RORγt activity (54) and that inactivation of FoxO1 is essential for Tfh cell differentiation (55). Therefore, FoxO1 inactivation arising from genetic defects in both TET2 and RhoA could lead to an imbalance in effector T cells to induce inflammatory-like phenotypes such as those we observed in recipient mice after adoptive T cell transfer.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…Bcl6 plays a central role in Tfh cell differentiation,115, 137, 138 but other transcription factors that act upstream and downstream of Bcl6 are also required (reviewed in 139). These include lymphoid enhancer‐binding factor 1 (LEF‐1) and T‐cell‐specific transcription factor 1 (TCF‐1), which act upstream of Bcl6 to promote Tfh cell differentiation140, 141, 142; basic leucine zipper transcription factor ATF‐like (Batf), which positively regulates Bcl6 and is important for IL‐4 expression143; interferon regulatory factor 4 (IRF4), which drives differentiation of IL‐12‐stimulated CD4 T cells to Tfh rather than Th1 cells144; achaete‐scute homolog 2 (Ascl2), which induces CXCR5 expression145; c‐Maf, which enhances expression of CXCR5, IL‐21, and IL‐4146; signal transducer and activator of transcription (STAT)s, STAT3 and 4 being particularly important for human Tfh cell differentiation and regulation of IL‐21 expression by human CD4 + T cells121, 147; and forkhead box protein O1 (FOXO1), which can both promote and inhibit Tfh cell differentiation 148. In addition, Tfh cell differentiation is regulated by microRNAs including members of the miRNA‐17‐92 family 149, 150.…”

Somatic mutation-associated T follicular helper cell elevation in lung adenocarcinoma

“…13 Of note, BCL6 , encoding the defining transcription factor for Tfh differentiation, showed no elevation in tumour tissue nor did TCF7 (encoding TCF1), PRDM1 (BLIMP-1), or ICOS (ICOS) (Fig S1), all of which have been shown to regulate Tfh differentiation via BCL6 and other key transcription factors. 20,21 ICOS was in fact reduced in tumour tissue, possibly due to the transient and temporally-specific nature of ICOS-dependent Tfh promotion in the TLO. 21 In summary, in two independent lung cancer cohorts, we found that expression signatures of Tfh cells were upregulated in tumours and that expression of Tfh signature genes was able to distinguish tumours from non-malignant tissue.…”

“…20,21 ICOS was in fact reduced in tumour tissue, possibly due to the transient and temporally-specific nature of ICOS-dependent Tfh promotion in the TLO. 21 In summary, in two independent lung cancer cohorts, we found that expression signatures of Tfh cells were upregulated in tumours and that expression of Tfh signature genes was able to distinguish tumours from non-malignant tissue.…”