Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1

Bothur, Evita; Raifer, Hartmann; Haftmann, Claudia; Stittrich, Anna-Barbara; Brüstle, Anne; Brenner, Dirk; Bollig, Nadine; Bieringer, Maria; Kang, Cholho; Reinhard, Katharina; Camara, Bärbel; Huber, Magdalena; Visekruna, Alexander; Steinhoff, Ulrich; Repenning, Antje; Bauer, Uta‐Maria; Sexl, Veronika; Radbruch, Andreas; Sparwasser, Tim; Mashreghi, Mir‐Farzin; Mak, Tak W.; Lohoff, Michael

doi:10.1038/ncomms9576

Cited by 27 publications

(24 citation statements)

References 59 publications

(102 reference statements)

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“…The transcription factor Foxo1 plays a crucial role in regulating T-cell activation, as well as the development and function of Tregs (Hedrick et al, 2012;Ouyang and Li, 2011). Several downstream mediators of Foxo1 have been identified in Tregs in mice, including Foxp3 and CTLA-4 (Bothur et al, 2015;Kerdiles et al, 2010;Ouyang et al, 2010). Foxo1 activation induces Foxp3 expression, which is essential for (Harada et al, 2010;Ohkura and Sakaguchi, 2010).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Akt-FOXO1 Pathway Leads to Dysfunction of Regulatory T Cells in Patients with Psoriasis

Lei

Yang

et al. 2019

Journal of Investigative Dermatology

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Psoriasis is a T lymphocyteedriven systemic inflammatory disease. Regulatory T cells (Tregs) are essential for establishing and maintaining immune tolerance. In this study, we found that patients with psoriasis and healthy controls had comparable percentages of circulating CD4 þ CD25 þ FOXP3 þ Tregs, but psoriatic Tregs had reduced suppressive function. Thereafter, mRNA arrays were performed to study the gene expression profile of psoriatic Tregs. Psoriatic Tregs expressed high levels of a T helper type 1elike transcription factor and cytokines such as T-bet and IFN-g. Furthermore, we found that FOXO1 can bind to the promoter of TBX21 to inhibit its expression, thus keeping the suppressive function of Tregs. However, an increase in protein kinase Bemediated phosphorylation of FOXO1 was observed in psoriatic Tregs, which subsequently caused FOXO1 inactivation by nuclear exclusion. In addition, incubation of healthy Tregs with psoriatic serum led to the activation of protein kinase B, nuclear exclusion of FOXO1, and the loss of FOXO1 transcription activity. The role of FOXO1 in regulating the function of Tregs was corroborated using a psoriasis-like mouse model in which Foxo1-deficient Tregs failed to protect mice from developing psoriasis. In conclusion, our findings reveal that the dysregulation of the protein kinase BeFOXO1 pathway may be a critical cause of Treg dysfunction in psoriasis.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of Akt-FOXO1 Pathway Leads to Dysfunction of Regulatory T Cells in Patients with Psoriasis

Lei

Yang

et al. 2019

Journal of Investigative Dermatology

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“…48,49 FOXO proteins regulate several aspects of lymphocyte function, including lymphocyte development, cytokine expression, gene recombination, and homing. 50 FOXO1 is needed for the survival of naive T cells and homing to secondary lymphoid organs 51 by regulating the expression of L-selectin and sphingosine-1-phosphate receptor 1 ( S1pr1 ), which are important for lymphocyte transit to and from lymphatic tissue.…”

Section: T Cellsmentioning

confidence: 99%

“…60 Constitutively active FOXO1 and STAT5 (with high TGF-β and low IL-6) were shown to rescue this autoimmune phenotype. 48 However, it is important to note that, in diabetic conditions, the relationship between FOXO1 and TGF-β1 changes. FOXO1 in a hyperglycemic environment fails to bind to the TGF-β1 promoter and fails to upregulate TGF-β1 transcription.…”

Section: T Cellsmentioning

confidence: 99%

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

et al. 2017

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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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“…Lack of Foxo1 not only compromises iTreg cell development but also leads to the appearance of cells with a Th1 phenotype in iTreg cell differentiation cultures . This is because Foxo1, the activity of which is reinforced by the iTreg cell differentiation cytokine TGF‐ β , is required to maintain Foxp3 expression, which otherwise would be lost as a consequence of the TCR signalling that is required for iTreg cell differentiation . Ikaros null CD4 T cells also demonstrate an inability to attain the iTreg cell fate, and instead appear to attain the phenotype of effector T helper cells (unpublished data, P. Agnihotri and S. Winandy).…”

Section: Discussionmentioning

confidence: 99%

Lack of Ikaros cripples expression of Foxo1 and its targets in naive T cells

et al. 2017

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Ikaros is a transcription factor that regulates lymphocyte development from the level of the haematopoietic stem cell. Lack of Ikaros reduces the ability of progenitor cells to commit to the T-cell lineage, resulting in reduced numbers of early thymic T-cell progenitors and mature T cells. Mature CD4 T cells that lack Ikaros have defects in proliferation, T helper cell differentiation, cytokine expression and the ability to become anergic. A role for Ikaros in the naive T cell has not yet been identified. The receptors interleukin-7 receptor α (IL-7Rα) and l-selectin are important for ensuring survival and proper homing of naive T cells, respectively. Here we show that lack of Ikaros leads to reduced expression of these receptors in naive T cells, which impacts their ability to home and survive in response to IL-7. We define the mechanism underlying this phenotype as a requirement for Ikaros in maintenance of expression of Foxo1, a transcriptional regulator that is required for their expression. We also demonstrate that CD4 T cells lacking Ikaros are significantly crippled in their ability to become induced regulatory T cells, a phenotype also linked to reduced Foxo1 expression. Finally, we show that restoring Ikaros function to Ikaros-deficient CD4 T cells increases levels of Foxo1 message. Together, these studies define, for the first time, a role for Ikaros in naive T cells and establish it as the first transcriptional regulator required for maintaining levels of Foxo1 gene expression in these cells.

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Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1

Cited by 27 publications

References 59 publications

Dysregulation of Akt-FOXO1 Pathway Leads to Dysfunction of Regulatory T Cells in Patients with Psoriasis

Dysregulation of Akt-FOXO1 Pathway Leads to Dysfunction of Regulatory T Cells in Patients with Psoriasis

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

Lack of Ikaros cripples expression of Foxo1 and its targets in naive T cells

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