Implications for Gene Therapy-Limiting Expression of IL-2R gamma(c) Delineate Differences in Signaling Thresholds Required for Lymphocyte Development and Maintenance

X-linked SCID patients are deficient in functional IL-2R gamma(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-2R gamma(c) gene therapy have T cells develop; however, their NK cell numbers remain low, suggesting antiviral responses may be compromised. Similarly, IL-2R gamma(-/-)(c) mice reconstituted with IL-2R gamma(c) developed few NK cells, and reconstituted T cells exhibited defective proliferative responses suggesting incomplete recovery of IL-2R gamma(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-2R gamma(-/-)(c) mice reconstituted with limiting amounts of IL-2R gamma(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-2R gamma(c) levels increased cytokine-induced STAT5 phosphorylation in both populations and increased NK cell proliferation demonstrating that IL-2R gamma(c) levels are limiting. In addition, although the half-lives of both NK and T cells expressing intermediate levels of IL-2R gamma(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-2R gamma(c) signaling thresholds for lymphocyte development and proliferation making functional monitoring imperative during gene therapy. Further, our findings suggest that IL-2R gamma(c) reconstituted T cells may persist more efficiently than NK cells due to compensation for suboptimal IL-2R gamma(c) signaling by the TCR. The Journal of Immunology, 2010, 185: 1393-1403.

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