Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS)

Kotsianidis, Ιoannis; Bouchliou, Irene; Nakou, Evangelia; Spanoudakis, Emmanuil; Margaritis, Dimitrios; Christophoridou, Anna V.; Anastasiades, Athanasios; Tsigalou, Christina; Bourikas, George; Karadimitris, Anastasios; Tsatalas, Constantinos

doi:10.1038/leu.2008.333

Cited by 130 publications

(106 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…28,37 It has recently been shown that T-Regulatory cells in early MDS, in contrast to advanced MDS, have a reduced ability to suppress immune responses and, through reduced expression of CXCR4, impaired bone marrow trafficking. 35 In agreement with these findings, we found that chemokine signaling through CXCR4 was deregulated in RA, with CXCR4 being down-regulated in RA by approximately 50% compared with healthy controls in our study. Genes in regular font are expressed at lower levels in À7/del7q compared with healthy controls, whereas genes in bold font are expressed at higher levels in À7/del7q compared with healthy controls.…”

Section: Deregulated Pathways In Myelodysplastic Syndromessupporting

confidence: 81%

“…There is mounting evidence, such as the presence of autoreactive T-cell clones and increased levels of preapoptotic cytokines, suggesting that immune deregulation, especially in early MDS, results in an autoimmune process leading to ineffective hematopoiesis and bone marrow failure, whereas advanced MDS is characterized by the immune evasion and selective growth advantage of the malignant clone. 35,36 In accord with this hypothesis, we have found that among the most significantly deregulated gene pathways in RA are 'immunodeficiency signaling,' 'B-cell receptor signaling,' 'IL4 signaling' and 'chemokine signaling.' The 'primary immunodeficiency signaling' pathway was the most significantly deregulated pathway in RA.…”

Section: Deregulated Pathways In Myelodysplastic Syndromessupporting

confidence: 57%

See 1 more Smart Citation

Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

et al. 2010

View full text Add to dashboard Cite

To gain insight into the molecular pathogenesis of the myelodysplastic syndromes (MDS), we performed global gene expression profiling and pathway analysis on the hematopoietic stem cells (HSC) of 183 MDS patients as compared with the HSC of 17 healthy controls. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathways. Among the most significantly deregulated gene pathways in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of DNA damage response and checkpoint pathways. We have identified distinct gene expression profiles and deregulated gene pathways in patients with del(5q), trisomy 8 or À7/del(7q). Patients with trisomy 8 are characterized by deregulation of pathways involved in the immune response, patients with À7/del(7q) by pathways involved in cell survival, whereas patients with del(5q) show deregulation of integrin signaling and cell cycle regulation pathways. This is the first study to determine deregulated gene pathways and ontology groups in the HSC of a large group of MDS patients. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype and give new insights into the molecular pathogenesis of this disorder, thereby providing new targets for therapeutic intervention.

show abstract

Section: Deregulated Pathways In Myelodysplastic Syndromessupporting

confidence: 81%

Section: Deregulated Pathways In Myelodysplastic Syndromessupporting

confidence: 57%

Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

et al. 2010

View full text Add to dashboard Cite

show abstract

“…[8][9][10][11] There is also accumulating evidence that impaired function of CD4 ϩ CD25 ϩ regulatory T cells (Tregs) has been implicated in the development of several common autoimmune diseases, 8,10 myelodysplastic syndromes, 12 and AA. 13 Until now, the only report of Treg abnormality in AA has shown that the numbers of circulating Tregs decreased in most patients.…”

Section: Introductionmentioning

confidence: 99%

Intrinsic impairment of CD4+CD25+ regulatory T cells in acquired aplastic anemia

Shi

et al. 2012

Blood

118

View full text Add to dashboard Cite

IntroductionAcquired aplastic anemia (AA), characterized by pancytopenia in peripheral blood (PB) and bone marrow (BM) hypoplasia, is a bone marrow failure syndrome attacked by autologous T cells, such as CD8 ϩ cytotoxic T cells, CD4 ϩ Th1 cells, and Th17 cells, on BM hematopoietic progenitors. [1][2][3][4] Hematopoiesis recovery after successful immunosuppressive treatment provided powerful evidence for the core role of the immune-mediated destruction of hematopoietic progenitor/stem cells. Mechanisms of immunemediated destruction of hematopoiesis include Th1 polarization response conferring immoderate production of inhibitory cytokines such as interferon-␥ (IFN-␥), tumor necrosis factor-␣ (TNF-␣), and interleukin-2 (IL-2), direct toxicity to autologous CD34 ϩ cells by T-cell populations, and Th17 immune response. [4][5][6][7] In that sense, AA is a specific autoimmune disease because of aberrant T-cell immune homeostasis and BM is the main target organ.It is now well established that CD4 ϩ T-cell subpopulations constitutively expressing the surface protein CD25 and the transcription factor FoxP3 are indispensable for the maintenance of immunologic self-tolerance and immunosuppression. [8][9][10][11] There is also accumulating evidence that impaired function of CD4 ϩ CD25 ϩ regulatory T cells (Tregs) has been implicated in the development of several common autoimmune diseases, 8,10 myelodysplastic syndromes, 12 and AA. 13 Until now, the only report of Treg abnormality in AA has shown that the numbers of circulating Tregs decreased in most patients. Meanwhile, almost all patients had low levels of nuclear factor of activated T cells, cytoplasmic 2 (NFAT1/ NFATc2) which could explain decreased FoxP3 expression in Tregs from AA patients. 13 But little is known regarding the function of Tregs in AA.Physiologically, induction of immune tolerance and suppression of autoreactive effector T-cell proliferation were the critical function of CD4 ϩ CD25 ϩ Tregs through cell contact-inhibition mechanisms and/or production of inhibitory cytokine. Furthermore, BM is a reservoir for CD4 ϩ CD25 ϩ Tregs that home to and are retained in BM through the stromal-derived factor-1␣ (SDF-1␣)/ CXCR4 signal. 14 Previous data demonstrated that the only way for Tregs homing to BM was via the SDF-1␣/CXCR4 signal. 14,15 It was believed that CXCR4 was the only receptor of SDF-1␣ for years. However, several reports recently provided evidence that SDF-1␣ also bound to another 7 transmembrane span receptor CXCR7. 16,17 Thus, the role of the SDF-1␣/CXCR4 axis in regulating Treg trafficking between BM and PB becomes more complex. Combined with the fact that BM is the target organ attacked by autoreactive effector T cells leading to hematopoiesis destruction, we hypothesized that Tregs in AA might have impaired homing potential to BM so as to be less efficient to suppress the effector T-cell proliferation and Th1-type cytokine production. We also hypothesized that Tregs in AA had intrinsic deficiencies of immunosuppression for autologous effector T...

show abstract

“…Leukemiainitiating-cells have also been associated with a mast cell signature; the IL2/CD25 axis may serve as a key regulator in leukemic cell activation [36]. As with leukemia, T-reg functionality is distorted in MDS; T-reg receptor profiles as well as migratory and homing capacities to the bone marrow are altered to favor LSC development [37]. Both MDS and leukemia are marked by unique cytokine and chemokine expression patterns [9] and it is likely that this alters the communication landscape between immune cells, stem cells, and stromal cells of the hematopoietic system.…”

Section: Fig 1 a Immune Cells Act As Homeostatic Plasticizers Of Thementioning

confidence: 99%

Regulation of normal and leukemic stem cells through cytokine signaling and the microenvironment

et al. 2017

View full text Add to dashboard Cite

Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS)

Cited by 130 publications

References 49 publications

Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

Intrinsic impairment of CD4+CD25+ regulatory T cells in acquired aplastic anemia

Regulation of normal and leukemic stem cells through cytokine signaling and the microenvironment

Contact Info

Product

Resources

About