{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:32:41Z","timestamp":1791243161826,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2010,8,1]],"date-time":"2010-08-01T00:00:00Z","timestamp":1280620800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>X-linked SCID patients are deficient in functional IL-2R\u03b3c 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-2R\u03b3c gene therapy have T cells develop; however, their NK cell numbers remain low, suggesting antiviral responses may be compromised. Similarly, IL-2R\u03b3c\u2212\/\u2212 mice reconstituted with IL-2R\u03b3c developed few NK cells, and reconstituted T cells exhibited defective proliferative responses suggesting incomplete recovery of IL-2R\u03b3c 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-2R\u03b3c\u2212\/\u2212 mice reconstituted with limiting amounts of IL-2R\u03b3c. Reconstitution resulted in lower IL-2\/-15\u2013mediated 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-2R\u03b3c levels increased cytokine-induced STAT5 phosphorylation in both populations and increased NK cell proliferation demonstrating that IL-2R\u03b3c levels are limiting. In addition, although the half-lives of both NK and T cells expressing intermediate levels of IL-2R\u03b3c 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-2R\u03b3c signaling thresholds for lymphocyte development and proliferation making functional monitoring imperative during gene therapy. Further, our findings suggest that IL-2R\u03b3c reconstituted T cells may persist more efficiently than NK cells due to compensation for suboptimal IL-2R\u03b3c signaling by the TCR.<\/jats:p>","DOI":"10.4049\/jimmunol.0903528","type":"journal-article","created":{"date-parts":[[2010,7,1]],"date-time":"2010-07-01T03:07:48Z","timestamp":1277953668000},"page":"1393-1403","source":"Crossref","is-referenced-by-count":15,"title":["Implications for Gene Therapy-Limiting Expression of IL-2R\u03b3c Delineate Differences in Signaling Thresholds Required for Lymphocyte Development and Maintenance"],"prefix":"10.1093","volume":"185","author":[{"given":"Selinda J","family":"Orr","sequence":"first","affiliation":[{"name":"Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Roessler","sequence":"additional","affiliation":[{"name":"Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Quigley","sequence":"additional","affiliation":[{"name":"Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Chan","sequence":"additional","affiliation":[{"name":"Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill W","family":"Ford","sequence":"additional","affiliation":[{"name":"Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldine M","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel W","family":"McVicar","sequence":"additional","affiliation":[{"name":"Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2010,8,1]]},"reference":[{"key":"2025032411435930000_r1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1111\/j.0105-2896.2004.00203.x","article-title":"Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways","volume":"202","author":"Kovanen","year":"2004","journal-title":"Immunol. 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