Implications for gene therapy-limiting expression of IL-2R gamma c delineate differences in signaling thresholds required for lymphocyte development and maintenance.
Implications for gene therapy-limiting expression of IL-2R gamma c delineate differences in signaling thresholds required for lymphocyte development and maintenance.
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DOI：
10.4049/jimmunol.0903528
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发表时间：
2010-08-01
期刊：
影响因子：
--
通讯作者：
McVicar DW
中科院分区：
文献类型：
--
作者：
Orr SJ;Roessler S;Quigley L;Chan T;Ford JW;O'Connor GM;McVicar DW
X连锁的SCID患者缺乏功能性IL-2 R γc，导致IL-2/IL-4/IL-7/IL-9/IL-15/IL-21信号传导的丧失以及缺乏NK和成熟T细胞。接受IL-2 R γc基因治疗的患者有T细胞发育;然而，他们的NK细胞数量仍然很低，这表明抗病毒反应可能会受到影响。同样，用IL-2 R γc重建的IL-2 R γc−/−小鼠产生的NK细胞很少，重建的T细胞表现出有缺陷的增殖反应，表明IL-2 R γc信号传导的恢复不完全。考虑到向具有较弱启动子的自失活长末端重复序列的转变以控制白血病的风险，我们评估了用有限量的IL-2 R γc重建的IL-2 R γc−/−小鼠中的NK和T细胞数量和功能。重组导致NK和T细胞中IL-2/−15介导的STAT 5磷酸化和增殖降低。然而，TCR共刺激恢复了精氨酸驱动的T细胞增殖到野生型水平。改善IL-2 R γc水平的载体修饰增加了两个群体中的精氨酸诱导的STAT 5磷酸化，并增加了NK细胞增殖，表明IL-2 R γc水平是有限的。此外，尽管与野生型细胞相比，表达中等水平IL-2 R γc的NK细胞和T细胞的半衰期均降低，但NK细胞半衰期的降低比T细胞严重得多。总的来说，这些数据表明淋巴细胞发育和增殖的不同IL-2 R γc信号传导阈值使得在基因治疗期间必须进行功能监测。此外，我们的研究结果表明，由于TCR对次优IL-2 R γc信号传导的补偿，IL-2 R γc重建的T细胞可能比NK细胞更有效地持续存在。
X-linked SCID patients are deficient in functional IL-2Rγc 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-2Rγc gene therapy have T cells develop; however, their NK cell numbers remain low, suggesting antiviral responses may be compromised. Similarly, IL-2Rγc−/− mice reconstituted with IL-2Rγc developed few NK cells, and reconstituted T cells exhibited defective proliferative responses suggesting incomplete recovery of IL-2Rγc 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-2Rγc−/− mice reconstituted with limiting amounts of IL-2Rγc. 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-2Rγc levels increased cytokine-induced STAT5 phosphorylation in both populations and increased NK cell proliferation demonstrating that IL-2Rγc levels are limiting. In addition, although the half-lives of both NK and T cells expressing intermediate levels of IL-2Rγc 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-2Rγc signaling thresholds for lymphocyte development and proliferation making functional monitoring imperative during gene therapy. Further, our findings suggest that IL-2Rγc reconstituted T cells may persist more efficiently than NK cells due to compensation for suboptimal IL-2Rγc signaling by the TCR.
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影响因子：
158.5
作者：
Hacein-Bey-Abina, S;Le Deist, F;Leiva, L
通讯作者：
Leiva, L
影响因子：
32.4
作者：
Bakker, ABH;Hoek, RM;Lanier, LL
通讯作者：
Lanier, LL
白介素（IL）-15R [alpha] - 缺陷的天然杀伤细胞在正常但IL-15R [alpha]缺陷小鼠中生存。
影响因子：
15.3
作者：
Koka, R;Burkett, PR;Chien, M;Chai, S;Chan, F;Lodolce, JP;Boone, DL;Ma, A
通讯作者：
Ma, A
DOI：
10.1084/jem.191.5.771
发表时间：
2000-03-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kennedy MK;Glaccum M;Brown SN;Butz EA;Viney JL;Embers M;Matsuki N;Charrier K;Sedger L;Willis CR;Brasel K;Morrissey PJ;Stocking K;Schuh JC;Joyce S;Peschon JJ
通讯作者：
Peschon JJ
影响因子：
20.3
作者：
Cooper, MA;Bush, JE;Caligiuri, MA
通讯作者：
Caligiuri, MA