The Role of Forkhead Box 1 (FOXO1) in the Immune System: Dendritic Cells, T Cells, B Cells, and Hematopoietic Stem Cells

Abstract

Forkhead box-O (FOXO) transcription factors have a fundamental role in the development and differentiation of immune cells. FOXO1 and FOXO3 are FOXO members that are structurally similar and bind to the same conserved consensus DNA sequences to induce transcription. FOXO1 has been studied in detail in the activation of dendritic cells (DCs), where it plays an important role through the regulation of target genes such as ICAM-1, CCR7, and the integrin αvβ3. FOXO1 is activated by bacteria challenge in DCs and promotes DC bacterial phagocytosis, migration, homing to lymph nodes, DC stimulation of CD4+ T cells and resting B cells, and antibody production. Deletion of FOXO1 in DCs enhances susceptibility to bacteria-induced periodontal disease. FOXO1 and FOXO3 maintain naive T cell quiescence and survival. FOXO1 and FOXO3 enhance the formation of regulatory T cells and inhibit the formation of T-helper 1 (Th1) and Th17 cells. FOXO1 promotes differentiation, proliferation, survival, immunoglobulin gene rearrangement, and class switching in B cells, but FOXO3 has little effect. Both FOXO1 and FOXO3 are important in the maintenance of hematopoietic stem cells by protecting them from oxidative stress. This review examines FOXO1/FOXO3 in the adaptive immune response, key target genes, and FOXO inhibition by the phosphoinositide 3-kinase/AKT pathway.

FIG. 1:

FOXO1 regulates activation and function of dendritic cells. (A) PRRs such as TLRs and cytokine receptors activate FOXO1 in DCs. FOXO1 up-regulates the expression of target genes ICAM1, αvβ3, APRIL, BAFF, Ccr7, CD80, CD86, IL-6, IL12, IFN-γ, and TNF-α while decreasing IL-10. This leads to increased homing of DCs to the lymph nodes and bacteria-infected tissue. It also increases the immnune response: antigen presentation, T and B cell activation, plasma cell numbers, and inflammation. The role of FOXO3 in DCs has not been well studied. (B) Pattern recognition receptors and cytokine receptor stimulation initiates a signaling cascade to activation of FOXO1 that involves the MAPK pathway. Activated FOXO1 can bind to the promoter region of target genes and regulate transcription. AKT is a major downstream target of PI3K that functions as a negative regulator of FOXO1. Stimulation of mTOR activates AKT to reduce FOXO1 activity and prevent a hyperinflammatory response.

FIG. 2:

FOXO1 is highly expressed in Tregs. FOXO1 can induce the expression of Foxp3, Ctla4, and CCR7 to increase the formation of Tregs and enhance Treg function. FOXO1 induces a transcriptome that is distinct from that induced by Foxp3. The effect of FOXO1 is to decrease effector Th cell formation, increase Treg differentiation, and increase the number of Tregs.

FIG. 3:

FOXO1/3 interferes with Th17 effector cell formation. Antigen presentation stimulates the TCR and silences FOXO1/3 through PI3K/AKT and SGK1. FOXO1/3 inhibits IL-23R and RORγt expression to inhibit Th17 cell differentiation. For Th17 cells to form, it is necessary to block FOXO1/3 activity.

FIG. 4:

FOXO1 increases memory T-cell formation. FOXO1 increases expression of CCR7, IL7R, BCL2, Sell, and Tcf7, which leads to increased memory T-cell formation and function. FOXO1 can decrease Tbet, which facilitates memory cell differentiation. FOXO3 plays a role in the maintenance of memory T cells.