Deficient IFN-  Expression in Umbilical Cord Blood (UCB) T Cells Can Be Rescued by IFN- -Mediated Increase in NFATc2 Expression

Kadereit, Suzanne; Junge, Gwendolyn R.; Kleen, Thomas O.; Kozik, M.; Kaminski, Beth; Daum-Woods, Kathleen; Fu, Pingfu; Tary‐Lehmann, Magdalena; Laughlin, Mary J.

doi:10.1023/b:joci.0000010425.30967.0f

Cited by 5 publications

(5 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the signaling pattern, we have found that Cbl-b is induced in CB naive CD4 + T cells, providing more molecular evidence that these cells may become anergic upon stimulation. Importantly, our results do not exclude other factors in contributing to impaired IFN-γ gene expression, such increased DNA methylation of the IFN-γ gene (61), reduced levels of NFATc2 in unfractionated CB CD4 + T cells (62), and altered antigen-presenting cell function (63, 64). …”

Section: Discussioncontrasting

confidence: 58%

Human Neonatal Naive CD4+ T Cells Have Enhanced Activation-Dependent Signaling Regulated by the MicroRNA miR-181a

Palin

Ramachandran

Acharya

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Human neonates have reduced and delayed CD4+ T-cell immunity to certain pathogens compared to older children and adults, but the mechanisms for these developmental differences in immune function remain poorly understood. We investigated the hypothesis that impaired human neonatal CD4+ T-cell immunity was due to reduced signaling by naive CD4+ T cells following engagement of the αβ-TCR/CD3 complex and CD28. Surprisingly, calcium flux following engagement of CD3 was significantly higher in neonatal naive CD4+ T cells from umbilical cord blood compared to naive CD4+ T cells from adult peripheral blood. Enhanced calcium flux was also observed in adult CD4+ recent thymic emigrants. Neonatal naive CD4+ T cells also had higher activation-induced Erk phosphorylation. The microRNA miR-181a, which enhances activation-induced calcium flux in murine thymocytes, was expressed at significantly higher levels in cord blood naive CD4+ T cells compared to adult cells. Overexpression of miR-181a in adult naive CD4+ T cells increased activation-induced calcium flux, implying that the increased miR-181a levels of cord blood naive CD4+ T cells contributed to their enhanced signaling. In contrast, AP-1-dependent transcription, which is downstream of Erk and required for full T-cell activation, was decreased in cord blood naive CD4+ T cells compared to adult cells. Thus, cord blood naive CD4+ T cells have enhanced activation-dependent calcium flux, indicative of the retention of a thymocyte-like phenotype. Enhanced calcium signaling and Erk phosphorylation are decoupled from downstream AP-1-dependent transcription, which is reduced and likely contributes to limitations of human fetal and neonatal CD4+ T-cell immunity.

show abstract

Section: Discussioncontrasting

confidence: 58%

Human Neonatal Naive CD4+ T Cells Have Enhanced Activation-Dependent Signaling Regulated by the MicroRNA miR-181a

Palin

Ramachandran

Acharya

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…During primary stimulation, naive UCB CD4 þ T cells have reproducibly exhibited both reduced Th1-associated cytokine, specifically IFN-g and TNF-a, 43,44 as well as significant changes in the composition of the transcription factors NFAT1, AP1 and BACH2. 3 Therefore, UCB CD4 þ T cell has the unique response for the co-stimulation of normal IL-2 expression coupled with rapid proliferation, which could have significant physiological and clinical ramifications in the allogeneic setting.…”

Section: Bach2's Function In Ucb Cd4mentioning

confidence: 99%

Regulation of IL-2 expression by transcription factor BACH2 in umbilical cord blood CD4+ T cells

et al. 2008

View full text Add to dashboard Cite

On activation, umbilical cord blood (UCB) CD4þ T cells demonstrate reduced expression of tumor necrosis factor-a (TNF-a) and interferon-c (IFN-c), whereas maintaining equivalent interleukin-2 (IL-2) levels, as compared with adult peripheral blood (PB) CD4 þ T cells. Nuclear factor of activated T cells (NFAT1) protein, a transcription factor known to regulate the expression of IL-2, TNF-a and IFN-c, is reduced in resting and activated UCB CD4 þ T cells. In contrast, expression of Broad-complex-Tramtrack-Bric-a-Brac and Cap'n'collar homology 1 bZip transcription factor 2 (BACH2) was shown by gene array analyses to be increased in UCB CD4 þ T cells and was validated by qRT-PCR. Using chromatin immunoprecipitation, BACH2 was shown binding to the human IL-2 proximal promoter. Knockdown experiments of BACH2 by transient transfection of UCB CD4 þ T cells with BACH2 siRNA resulted in significant reductions in stimulated IL-2 production. Decreased IL-2 gene transcription in UCB CD4þ T cells transfected with BACH2 siRNA was confirmed by a human IL-2 luciferase assay. In summary, BACH2 maintains IL-2 expression in UCB CD4þ T cells at levels equivalent to adult PB CD4 þ T cells despite reduced NFAT1 protein expression. Thus, BACH2 expression is necessary to maintain IL-2 production when NFAT1 protein is reduced, potentially impacting UCB graft CD4þ T-cell allogeneic responses.

show abstract

“…Presently, enrichment for Hoechst-dim cells by flow sorting is not maintained after passage. Previous work has indicated that Hoechst-dim staining is a result of the presence of the ABCG2 receptor [37,38]. As shown in Figure 1E and 1F, human UCMS (hUCMS) cells showed the characteristic surface staining for the ABCG2 receptor and CD44.…”

Section: Flow Cytometry and Sorting Of Hoechst-dim Cellsmentioning

confidence: 83%

Human Umbilical Cord Matrix Stem Cells: Preliminary Characterization and Effect of Transplantation in a Rodent Model of Parkinson's Disease

et al. 2005

View full text Add to dashboard Cite

The umbilical cord contains an inexhaustible, noncontroversial source of stem cells for therapy. In the U.S., stem cells found in the umbilical cord are routinely placed into biohazardous waste after birth. Here, stem cells derived from human umbilical cord Wharton's Jelly, called umbilical cord matrix stem (UCMS) cells, are characterized. UCMS cells have several properties that make them of interest as a source of cells for therapeutic use. For example, they 1) can be isolated in large numbers, 2) are negative for CD34 and CD45, 3) grow robustly and can be frozen/thawed, 4) can be clonally expanded, and 5) can easily be engineered to express exogenous proteins. UCMS cells have genetic and surface markers of mesenchymal stem cells (positive for CD10, CD13, CD29, CD44, and CD90 and negative for CD14, CD33, CD56, CD31, CD34, CD45, and HLA-DR) and appear to be stable in terms of their surface marker expression in early passage (passages 4 -8). Unlike traditional mesenchymal stem cells derived from adult bone marrow stromal cells, small populations of UCMS cells express endoglin (SH2, CD105) and CD49e at passage 8. UCMS cells express growth factors and angiogenic factors, suggesting that they may be used to treat neurodegenerative disease. To test the therapeutic value of UCMS cells, undifferentiated human UCMS cells were transplanted into the brains of hemiparkinsonian rats that were not immune-suppressed. UCMS cells ameliorated apomorphine-induced rotations in the pilot test. UCMS cells transplanted into normal rats did not produce brain tumors, rotational behavior, or a frank host immune rejection response. In summary, the umbilical cord matrix appears to be a rich, noncontroversial, and inexhaustible source of primitive mesenchymal stem cells. STEM CELLS 2006;24:781-792

show abstract

Deficient IFN- Expression in Umbilical Cord Blood (UCB) T Cells Can Be Rescued by IFN- -Mediated Increase in NFATc2 Expression

Cited by 5 publications

References 45 publications

Human Neonatal Naive CD4+ T Cells Have Enhanced Activation-Dependent Signaling Regulated by the MicroRNA miR-181a

Human Neonatal Naive CD4+ T Cells Have Enhanced Activation-Dependent Signaling Regulated by the MicroRNA miR-181a

Regulation of IL-2 expression by transcription factor BACH2 in umbilical cord blood CD4+ T cells

Human Umbilical Cord Matrix Stem Cells: Preliminary Characterization and Effect of Transplantation in a Rodent Model of Parkinson's Disease

Contact Info

Product

Resources

About