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PubMed2004

Expression of FoxE4 and Rx visualizes the timing and dynamics of critical processes taking place during initial stages of vertebrate eye development.

Several transcription factors have a critical function during initial stages of vertebrate eye formation. In this paper, we discuss the role of the Rx subfamily of homeobox-containing genes in retinal development, and the role of the Foxe3 and FoxE4 subfamily of forkhead box-containing genes in lens development. Rx genes are expressed in the initial stages of retinal development and they play a critical role in eye formation. Elimination of Rx function in mice results in lack of eye formation. Abnormal eye development observed in the mouse mutation eyeless (ey1), the medakatemperature-sensitive mutation eyeless (el), and the zebrafish mutation chokh are caused by abnormal regulation or function of Rx genes. In humans, a mutation in Rx leads to anophthalmia. In contrast, Foxe3 and FoxE4 genes are expressed in the lens and they play an essential role in its formation. Mutations in the Foxe3 gene are the cause of the mouse mutation dysgenetic lens (dyl) and in humans, mutation in FOXE3 leads to anterior segment dysgenesis and cataracts. Since Rx and FoxE4 are expressed in the earliest stages of retina and lens development, their expression visualizes the timing and dynamics of the crucial processes that comprise eye formation. In this paper we present a model of eye development based on the expression pattern of these two genes.

Animals↗
PubMed2005

Reduced wall compliance suppresses Akt-dependent apoptosis protection stimulated by pulse perfusion.

Reduced arterial compliance and increased pulse pressure are common and major risk factors for cardiovascular disease. Here, we reveal a novel mechanism whereby loss of wall distensibility blunts endothelial cell protection to oxidant stress-induced apoptosis. Bovine aortic endothelial cells cultured in compliant or stiff silastic tubes were pulse perfused by arterial pressure/flow waveforms generated by a servo-pump. Pulse perfusion induced time-dependent Akt activation peaking >6-fold after 2 hours in compliant tubes and a similar time course but half the magnitude in stiff tubes. This was accompanied by quantitatively similar disparities in phosphoinositide-3 kinase activation and in Akt-stimulated suppressors of apoptosis: glycogen synthase kinase-3beta, forkhead, and Bad. Cells perfused in compliant tubes had twice the protection against H2O2-stimulated apoptosis than those in stiffer tubes. This protection was lost by pretreatment with an Akt inhibitor and restored in cells transfected with myristoylated Akt yet perfused in stiff tubes. Shear and stretch Akt signaling coupled to different upstream pathways as inhibition of vascular endothelial growth factor receptor 2 (VEGF2R) or disruption of caveolae blocked steady and pulse flow-mediated activation, yet did not suppress phosphorylated Akt induced by pulse perfusion in compliant tubes (concomitant stretch). Unlike Akt, reactive oxygen species, activated nuclear factor kappaB, and suppression of H2O2-stimulated c-Jun-N-terminal kinase activity were similar in pulse-perfused compliant and stiff tubes. Thus, cyclic endothelial cell stretch by pulse perfusion enhances Akt-dependent antiapoptosis above that induced by steady or phasic shear stress and, unlike the latter, signals via a VEGF2R/caveolae-independent pathway. Enhancing this stretch pathway may prove useful for improving endothelial function in stiff arteries.

Animals↗
PubMed2001

Myocardial Akt activation and gender: increased nuclear activity in females versus males.

Cardiovascular disease risk is higher in men than women, but the basis for this discrepancy remains controversial. Estrogenic stimulation of the myocardium or isolated cardiomyocytes has been purported to exert multiple beneficial effects associated with inhibition of maladaptive responses to pathogenic insults. This report describes a significant difference between the sexes in myocardial activation of Akt, a protein kinase that regulates a broad range of physiological responses including metabolism, gene transcription, and cell survival. We find that young women possess higher levels of nuclear-localized phospho-Akt(473) relative to comparably aged men or postmenopausal women. Both localization of phospho-Akt(473) in myocardial nuclei of sexually mature female mice versus males and Akt kinase activity in nuclear extracts of hearts from female mice versus males are elevated. Cytosolic localization of phospho-forkhead, a downstream nuclear target of Akt, is also increased in female relative to male mice, suggesting a potential mechanism for cardioprotective nuclear signaling resulting from Akt activation. Phospho-Akt(473) levels and localization at cardiac nuclei are similarly increased in transgenic mice with myocardium-specific expression of insulin-like growth factor I, a proven stimulus for Akt activation. Phospho-Akt(473) is also localized to the nucleus of cultured cardiomyocytes after exposure to 17beta-estradiol or genistein (a phytoestrogen in soy protein-based diets), and neonatal exposure of litters to genistein elevated nuclear phospho-Akt(473) localization. The activation of Akt in a gender-dependent manner may help explain differences observed in cardiovascular disease risk between the sexes and supports the potential beneficial effects of estrogenic stimulation.

Active Transport, Cell Nucleus↗
PubMed2005

CD4+CD25+ regulatory T lymphocytes in malignant pleural effusion.

BACKGROUND: Active suppression by CD4(+)CD25(+) regulatory T lymphocytes plays an important role in the downregulation of T-cell responses to foreign and self-antigens. OBJECTIVE: To analyze whether the CD4(+)CD25(+) regulatory T lymphocytes exist and function normally in malignant pleural effusion. METHODS: The percentages of CD4(+)CD25(+) T lymphocytes in pleural effusion and peripheral blood from patients with lung cancer with malignant effusion, pleural lavage and peripheral blood from patients with lung cancer without effusion, and peripheral blood from healthy control subjects were determined by flow cytometry. The expressions of forkhead transcription factor Foxp3 and cytotoxic lymphocyte-associated antigen-4 were also examined. CD4(+)CD25(+) and CD4(+)CD25(-) T cells from pleural effusion and peripheral blood were isolated, and were cultured to observe the effects of CD4(+)CD25(+) cells on proliferation response of CD4(+)CD25(-) T cells in vitro. MAIN RESULTS: There were increased numbers of CD4(+)CD25(+) T cells in malignant pleural effusion from patients with lung cancer compared with pleural lavage from patients with lung cancer without pleural effusion, and that these cells have constitutive high-level expression of Foxp3 and cytotoxic lymphocyte-associated antigen-4. Furthermore, CD4(+)CD25(+) T cells mediate potent inhibition of proliferation response of CD4(+)CD25(-) T cells, and anticytotoxic lymphocyte-associated antigen-4 monoclonal antibody could reduce the inhibitory activity of CD4(+)CD25(+) T cells. CONCLUSIONS: The increased CD4(+)CD25(+) T cells found in malignant pleural effusion express high levels of Foxp3 transcription factor and potently suppress the proliferation of CD4(+)CD25(-) T cells, and cytotoxic lymphocyte-associated antigen-4 is involved in the suppressive activity of pleural CD4(+)CD25(+) T cells.

Adult↗
PubMed2004

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy.

Programmed cell death pathways have been implicated in the mechanism by which neurons die following brief and prolonged seizures, but the significance of proapoptotic Bcl-2 family proteins in the process remains poorly defined. Expression of the death agonist Bcl-2-interacting mediator of cell death (Bim) is under the control of the forkhead in rhabdomyosarcoma (FKHR) transcription factors. This prompted us to examine the response of this pathway to experimental seizures and in hippocampi from patients with intractable temporal lobe epilepsy. A short period of status epilepticus in rats that damaged the hippocampus activated FKHR/FKHRL-1 and induced a significant increase in expression of Bim. Blocking of FKHR/FKHRL-1 dephosphorylation after seizures improved hippocampal neuronal survival in vivo, and Bim antisense oligonucleotides were neuroprotective against seizures in vitro. Inhibition of Akt increased the FKHR/Bim response and DNA fragmentation within the normally resistant cortex. Analysis of hippocampi from patients with intractable epilepsy revealed that Bim levels were significantly lower than in controls and FKHR was inhibited; we were able to reproduce these results experimentally in rats by evoking multiple brief, noninjurious electroshock seizures. We conclude that Bim expression may be a critical determinant of whether seizures damage the brain, and that its control may be neuroprotective in status epilepticus and epilepsy.

Animals↗
PubMed2004

A fork in the road of cell differentiation in the kidney tubule.

The collecting ducts of the kidney are composed of intercalated cells (responsible for acid/base transport), principal cells (mediating salt and water absorption), and inner medullary cells, which mediate all three types of transport. Forkhead box (Fox) genes are a large family of transcription factors that are important in cell-type specification during organogenesis. In this issue, Blomqvist et al. find that mice lacking Foxi1 have no intercalated cells in the kidney. The collecting ducts of the null mice contained primitive cells that expressed both intercalated cell and principal cell proteins, yet the acid/base transport function of the kidney was disrupted and the mice exhibited distal renal tubular acidosis. These findings suggest that Foxi1 plays a critical role in determining cell identity during collecting duct development.

Animals↗
PubMed2005

Virus-induced dysfunction of CD4+CD25+ T cells in patients with HTLV-I-associated neuroimmunological disease.

CD4(+)CD25(+) Tregs are important in the maintenance of immunological self tolerance and in the prevention of autoimmune diseases. As the CD4(+)CD25(+) T cell population in patients with human T cell lymphotropic virus type I-associated (HTLV-I-associated) myelopathy/tropical spastic paraparesis (HAM/TSP) has been shown to be a major reservoir for this virus, it was of interest to determine whether the frequency and function of CD4(+)CD25(+) Tregs in HAM/TSP patients might be affected. In these cells, both mRNA and protein expression of the forkhead transcription factor Foxp3, a specific marker of Tregs, were lower than those in CD4(+)CD25(+) T cells from healthy individuals. The virus-encoded transactivating HTLV-I tax gene was demonstrated to have a direct inhibitory effect on Foxp3 expression and function of CD4(+)CD25(+) T cells. This is the first report to our knowledge demonstrating the role of a specific viral gene product (HTLV-I Tax) on the expression of genes associated with Tregs (in particular, foxp3) resulting in inhibition of Treg function. These results suggest that direct human retroviral infection of CD4(+)CD25(+) T cells may be associated with the pathogenesis of HTLV-I-associated neurologic disease.

CD4-Positive T-Lymphocytes↗
PubMed2005

In vivo expansion of CD4CD45RO-CD25 T cells expressing foxP3 in IL-2-treated HIV-infected patients.

Administration of IL-2 to HIV-infected patients leads to expansion of a unique subset of CD4CD45ROCD25 cells. In this study, the origin, clonality, and function of these cells were investigated. Analysis of TCR excision circles revealed that the CD4CD45ROCD25 cells were the product of peripheral expansion but remained polyclonal as determined by TCR repertoire analysis. Phenotypically, these cells were distinct from naturally occurring Tregs; they exhibited intermediate features, between those of memory and naive cells, and had lower susceptibility to apoptosis than CD45ROCD25 or memory T cells. Studies of intracellular cytokine production and proliferation revealed that cytokine-expanded naive CD25 cells had low IL-2 production and required costimulation for proliferation. Despite elevated expression of forkhead transcription factor P3 (foxP3), they exerted only weak suppression compared with CD45ROCD25 cells (Tregs). In summary, in vivo IL-2 administration to HIV-infected patients leads to peripheral expansion of a population of long-lived CD4CD45ROCD25 cells that express high levels of foxP3 but exert weak suppressive function. These CD4CD25 cytokine-expanded naive cells, distinct from antigen-triggered cells and Tregs, play a role in the maintenance of a state of low turnover and sustained expansion of the CD4 T cell pool.

Adult↗
PubMed2006

Defective regulatory and effector T cell functions in patients with FOXP3 mutations.

The autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is caused by mutations in the forkhead box protein P3 (FOXP3) gene. In the mouse model of FOXP3 deficiency, the lack of CD4+ CD25+ Tregs is responsible for lethal autoimmunity, indicating that FOXP3 is required for the differentiation of this Treg subset. We show that the number and phenotype of CD4+ CD25+ T cells from IPEX patients are comparable to those of normal donors. CD4+ CD25high T cells from IPEX patients who express FOXP3 protein suppressed the in vitro proliferation of effector T cells from normal donors, when activated by "weak" TCR stimuli. In contrast, the suppressive function of CD4+ CD25high T cells from IPEX patients who do not express FOXP3 protein was profoundly impaired. Importantly, CD4+ CD25high T cells from either FOXP3+ or FOXP3- IPEX patients showed altered suppression toward autologous effector T cells. Interestingly, IL-2 and IFN-gamma production by PBMCs from IPEX patients was significantly decreased. These findings indicate that FOXP3 mutations in IPEX patients result in heterogeneous biological abnormalities, leading not necessarily to a lack of differentiation of CD4+ CD25high Tregs but rather to a dysfunction in these cells and in effector T cells.

Animals↗
PubMed2006

Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis.

Recent evidence has indicated that leptin, an adipocyte-secreted hormone belonging to the helical cytokine family, significantly influences immune and autoimmune responses. We investigate here the mechanisms by which in vivo abrogation of leptin effects protects SJL/J mice from proteolipid protein peptide PLP(139-151)-induced EAE, an animal model of MS. Blockade of leptin with anti-leptin Abs or with a soluble mouse leptin receptor chimera (ObR:Fc), either before or after onset of EAE, improved clinical score, slowed disease progression, reduced disease relapses, inhibited PLP(139-151)-specific T cell proliferation, and switched cytokine secretion toward a Th2/regulatory profile. This was also confirmed by induction of forkhead box p3 (Foxp3) expression in CD4 T cells in leptin-neutralized mice. Importantly, anti-leptin treatment induced a failure to downmodulate the cyclin-dependent kinase inhibitor p27 (p27) in autoreactive CD4 T cells. These effects were associated with increased tyrosine phosphorylation of both ERK1/2 and STAT6. Taken together, our data provide what we believe is a new molecular basis for leptin antagonism in EAE and envision novel strategies of leptin-based molecular targeting in the disease.

Animals↗
PubMed2006

IPEX and the role of Foxp3 in the development and function of human Tregs.

Genetic defects in the transcription factor forkhead box protein P3 (Foxp3) cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX). IPEX is thought to be due to a defect in naturally arising CD4+ Tregs. In this issue of the JCI, Bacchetta and colleagues demonstrate that patients with IPEX and missense mutations in Foxp3 provide insight into the role of various domains of Foxp3 in the development and function of Tregs (see the related article beginning on page 1713).

Animals↗
PubMed2007

Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis.

Wiskott-Aldrich syndrome protein (WASp) is essential for optimal T cell activation. Patients with WAS exhibit both immunodeficiency and a marked susceptibility to systemic autoimmunity. We investigated whether alterations in Treg function might explain these paradoxical observations. While WASp-deficient (WASp(-/-)) mice exhibited normal thymic Treg generation, the competitive fitness of peripheral Tregs was severely compromised. The total percentage of forkhead box P3-positive (Foxp3(+)) Tregs among CD4(+) T cells was reduced, and WASp(-/-) Tregs were rapidly outcompeted by WASp(+) Tregs in vivo. These findings correlated with reduced expression of markers associated with self-antigen-driven peripheral Treg activation and homing to inflamed tissue. Consistent with these findings, WASp(-/-) Tregs showed a reduced ability to control aberrant T cell activation and autoimmune pathology in Foxp3(-/-)Scurfy (sf) mice. Finally, WASp(+) Tregs exhibited a marked selective advantage in vivo in a WAS patient with a spontaneous revertant mutation, indicating that altered Treg fitness likely explains the autoimmune features in human WAS.

Adoptive Transfer↗
PubMed2004

Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome.

FOXP1 (Forkhead box-P1) is a winged-helix transcription factor that is differentially expressed in resting and activated B cells. FOXP1 expression has been demonstrated in a subset of diffuse large B-cell lymphomas (DLBCLs) and is more common in the nongerminal center (non-GC), activated B-cell type; however, its prognostic significance is uncertain. We analyzed presentation lymph nodes from 126 patients with nodal DLBCL, previously classified according to GC and BCL2 status, for FOXP1 protein expression using standard immunocytochemistry. Uniform high FOXP1 expression was demonstrated in 23 of 126 patients with DLBCL. This high level of expression was almost exclusively confined to patients who lacked the GC phenotype, who expressed MUM-1 and BCL2 in the absence of t(14; 18), and who were identified as a subgroup of patients with particularly poor outcomes in a group with already poor prognoses. The data presented suggest that high FOXP1 expression is an independent prognostic factor in DLBCL.

Biomarkers, Tumor↗
PubMed2005

Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine.

Globally suppressed T-cell function has been described in many patients with cancer to be a major hurdle for the development of clinically efficient cancer immunotherapy. Inhibition of antitumor immune responses has been mainly linked to inhibitory factors present in cancer patients. More recently, increased frequencies of CD4+CD25hi regulatory T cells (Treg cells) have been described as an additional mechanism reducing immunity. We assessed 73 patients with B-cell chronic lymphocytic leukemia (CLL) and 42 healthy controls and demonstrated significantly increased frequencies of cytotoxic T lymphocyte-associated protein 4 (CTLA4+)-, Forkhead box P3 (FOXP3+)-, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR+)-, CD62L+-, transforming growth factor beta1 (TGF-beta1+)-, interleukin 10 (IL-10+)-Treg cells in patients with CLL, with highest frequencies in untreated or progressing patients presenting with extended disease. Most surprisingly, in the majority of patients with CLL treated with fludarabine-containing therapy regimens the inhibitory function of Treg cells was decreased or even abrogated. In addition, frequencies of Treg cells were significantly decreased after therapy with fludarabine. In light of similar findings for cyclophosphamide the combination of fludarabine and cyclophosphamide might be further exploited in strategies reducing immunosuppression prior to cancer immunotherapy.

Adult↗
PubMed2006

Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion.

Thymus-derived CD4+ CD25+ regulatory T cells suppress autoreactive CD4+ and CD8+ T cells and thereby protect from autoimmunity. In animal models, adoptive transfer of CD4+ CD25+ regulatory T cells has been shown to prevent and even cure autoimmune diseases as well as pathogenic alloresponses after solid organ and stem-cell transplantations. We recently described methods for the efficient in vitro expansion of human regulatory T cells for clinical applications. We now demonstrate that only CCR7- and L-selectin (CD62L)-coexpressing cells within expanded CD4+ CD25high T cells maintain phenotypic and functional characteristics of regulatory T cells. Further analysis revealed that these cells originate from CD45RA+ naive cells within the CD4+ CD25high T-cell compartment, as only this subpopulation homogeneously expressed CD62L, CCR7, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and forkhead box P3 (FOXP3), produced no inflammatory cytokines and maintained robust suppressive activity after expansion. In contrast, cell lines derived from CD45RA- memory-type CD4+ CD25high T cells lost expression of lymph node homing receptors CCR7 and CD62L, contained interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) as well as IL-10-secreting cells, showed only moderate suppression and, most importantly, did not maintain FOXP3 expression. Based on these unexpected findings, we suggest that isolation and expansion of CD45RA+ naive CD4+ CD25high T cells is the best strategy for adoptive regulatory T (Treg)-cell therapies.

Antigens, CD↗
PubMed2005

Transforming growth factor-beta-induced regulatory T cells referee inflammatory and autoimmune diseases.

Naturally occurring CD4+CD25+ regulatory T cells mediate immune suppression to limit immunopathogenesis associated with chronic inflammation, persistent infections and autoimmune diseases. Their mode of suppression is contact-dependent, antigen-nonspecific and involves a nonredundant contribution from the cytokine transforming growth factor (TGF)-beta. Not only can TGF-beta mediate cell-cell suppression between the regulatory T cells and CD4+CD25- or CD8+ T cells, but new evidence also reveals its role in the conversion of CD4+CD25- T cells, together with TCR antigen stimulation, into the regulatory phenotype. Elemental to this conversion process is induction of expression of the forkhead transcription factor, Foxp3. This context-dependent coercion of naive CD4+ T cells into a powerful subset of regulatory cells provides a window into potential manipulation of these cells to orchestrate therapeutic intervention in diseases characterized by inadequate suppression, as well as a promising means of controlling pathologic situations in which excessive suppression dominates.

Animals↗
PubMed2006

A novel missense mutation in human TTF-2 (FKHL15) gene associated with congenital hypothyroidism but not athyreosis.

BACKGROUND: Thyroid dysgenesis is the most frequent cause of congenital hypothyroidism (CH), and its genetic basis is largely unknown. Hitherto, two mutations in the human thyroid transcription factor 2 (TTF-2) gene have been described in unrelated cases of CH with cleft palate, spiky hair, variable choanal atresia, and complete thyroid agenesis. Here, we describe a novel TTF-2 mutation in a female child resulting in syndromic CH in the absence of thyroid agenesis. RESULTS: The index case is homozygous for an arginine to cysteine mutation (R102C) of a highly conserved residue within the forkhead, DNA binding domain of TTF-2. Her consanguineous, heterozygous parents are unaffected, and the mutation was not detected in 100 control chromosomes. Consonant with its location, the R102C mutant TTF-2 protein showed loss of DNA binding and was transcriptionally inactive. CH in the proposita was associated with cleft palate, spiky hair, and bilateral choanal atresia. However, radiological studies showed the presence of thyroid tissue in a eutopic location. CONCLUSION: Our findings indicate that human thyroid development can occur despite loss of TTF-2 function and suggest that TTF-2 gene defects should also be considered in cases of syndromic CH without total athyreosis.

Amino Acid Sequence↗
PubMed2004

FoxO1a can alter cell cycle progression by regulating the nuclear localization of p27kip in granulosa cells.

Forkhead transcription factors of the FOXO family are important downstream targets of the phosphatidylinositol 3-kinase pathway, which has been shown to play a critical role in cell proliferation and cell survival. Activation of FOXOs can block cellular proliferation and drive cells into a quiescent state. In certain cell types, this cell cycle arrest is dependent on the transcriptional induction of the cell-cycle inhibitor p27kip. In granulosa cells, which go through an exponential growth phase during development of the ovarian follicle, we find that FoxO1a is a key regulator of the G1/S transition in these cells. Overexpression of a dominant-negative version of FoxO1a (Foxo1a-Delta256; a C-terminal truncation mutant that possesses a functional DNA-binding domain, but lacks a transactivation domain) causes a dramatic increase in S-phase cells (>8-fold increase by both DNA content and bromodeoxyuridine incorporation assays). Surprisingly, this is not dependent on transactivation of the p27kip gene. We provide evidence that when FoxO1a activity is impeded, p27kip protein is largely localized to the cytosol, suggesting that FoxO1a blocks cell cycle entry by altering the compartmentalization of p27kip within the cell, increasing its concentration in the nucleus. These studies demonstrate for the first time that FoxO1a can regulate p27kip nuclear localization.

Animals↗