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.

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“…Since the discovery of the first Forkhead gene in Drosophila in 1989, more than 100 members of the family have been identified [31]. The common feature of the Forkhead family is a conserved DNA-binding domain called Fox, which consists of three α-helices, three β-sheets and two loops that are referred to as wings [32,33]. Because of this feature, these transcription factors are called Forkhead/ winged helix transcription factors.…”

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“…2i). Of note, FOXO1 regulates oxidative stress responses, proliferation, cell survival, and apoptosis, and connects metabolic activity with immune response [38][39][40] .…”

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“…They concluded that a cascade involving kinase Mst-Foxo/nuclear factor 2 (Nrf2) signaling pathway is important for attenuating ROS-induced immune cell damage and pathological states including infection diseases. Up regurlation of Foxo3 was reported to modulate helper T cell quiescence [ 85 ] and increase T-lymphocyts apoptosis [ 86 ]. Bi et al [ 87 ] indicated that Foxo1, Foxo3 and Foxo4 are key genes in inhibiting lymphocyte cell proliferation of chicken infected with reticuloendotheliosis virus.…”