Implications for gene therapy-limiting expression of IL-2R c delineate differences in signaling thresholds required for lymphocyte development and maintenance

Orr, Selinda Jane, Roessler, S., Quigley, L., Chan, T., Ford, J. W., O'Connor, G. M. and McVicar, D. W. 2010. Implications for gene therapy-limiting expression of IL-2R c delineate differences in signaling thresholds required for lymphocyte development and maintenance. The Journal of Immunology 185 (3) , pp. 1393-1403. 10.4049/jimmunol.0903528

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Last Modified:	04 Jun 2017 08:35
URI:	https://orca.cardiff.ac.uk/id/eprint/80639

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