Linked Life Data

20592278

Source:http://linkedlifedata.com/resource/pubmed/id/20592278

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2010-7-27
pubmed:abstractText
X-linked SCID patients are deficient in functional IL-2Rgamma(c) leading to the loss of IL-2/IL-4/IL-7/IL-9/IL-15/IL-21 signaling and a lack of NK and mature T cells. Patients treated with IL-2Rgamma(c) gene therapy have T cells develop; however, their NK cell numbers remain low, suggesting antiviral responses may be compromised. Similarly, IL-2Rgamma(c)(-/-) mice reconstituted with IL-2Rgamma(c) developed few NK cells, and reconstituted T cells exhibited defective proliferative responses suggesting incomplete recovery of IL-2Rgamma(c) signaling. Given the shift toward self-inactivating long terminal repeats with weaker promoters to control the risk of leukemia, we assessed NK and T cell numbers and function in IL-2Rgamma(c)(-/-) mice reconstituted with limiting amounts of IL-2Rgamma(c). Reconstitution resulted in lower IL-2/-15-mediated STAT5 phosphorylation and proliferation in NK and T cells. However, TCR costimulation restored cytokine-driven T cell proliferation to wild-type levels. Vector modifications that improved IL-2Rgamma(c) levels increased cytokine-induced STAT5 phosphorylation in both populations and increased NK cell proliferation demonstrating that IL-2Rgamma(c) levels are limiting. In addition, although the half-lives of both NK and T cells expressing intermediate levels of IL-2Rgamma(c) are reduced compared with wild-type cells, the reduction in NK cell half-live is much more severe than in T cells. Collectively, these data indicate different IL-2Rgamma(c) signaling thresholds for lymphocyte development and proliferation making functional monitoring imperative during gene therapy. Further, our findings suggest that IL-2Rgamma(c) reconstituted T cells may persist more efficiently than NK cells due to compensation for suboptimal IL-2Rgamma(c) signaling by the TCR.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1550-6606
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
185
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1393-403
pubmed:meshHeading
pubmed-meshheading:20592278-Animals, pubmed-meshheading:20592278-Cell Differentiation, pubmed-meshheading:20592278-Cell Proliferation, pubmed-meshheading:20592278-Gene Expression Regulation, pubmed-meshheading:20592278-Gene Therapy, pubmed-meshheading:20592278-Interleukin Receptor Common gamma Subunit, pubmed-meshheading:20592278-Interleukin-15, pubmed-meshheading:20592278-Interleukin-2, pubmed-meshheading:20592278-Killer Cells, Natural, pubmed-meshheading:20592278-Mice, pubmed-meshheading:20592278-Mice, Inbred C57BL, pubmed-meshheading:20592278-Mice, Knockout, pubmed-meshheading:20592278-Mice, SCID, pubmed-meshheading:20592278-Phosphorylation, pubmed-meshheading:20592278-Receptors, Antigen, T-Cell, pubmed-meshheading:20592278-STAT5 Transcription Factor, pubmed-meshheading:20592278-Severe Combined Immunodeficiency, pubmed-meshheading:20592278-Signal Transduction, pubmed-meshheading:20592278-T-Lymphocyte Subsets, pubmed-meshheading:20592278-Transduction, Genetic
pubmed:year
2010
pubmed:articleTitle
Implications for gene therapy-limiting expression of IL-2R gamma c delineate differences in signaling thresholds required for lymphocyte development and maintenance.
pubmed:affiliation
Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, N.I.H., Intramural