NT-I7, a Long-Acting Interleukin-7 Molecule, Promotes T Cell Reconstitution Following Radiation Injury through Thymic-Dependent and Independent Pathways

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.126-126
• Main Authors: Zou, Yujing, Bardahl, Jonathan, Jiao, Yiqun, Yang, James, Dai, Danika, Wolfarth, Alexandra, Borgonia, Danielle, Lee, Byung Ha, Chen, Benny J.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-208493

Total body irradiation (TBI) causes suppression of hematopoiesis and T cell depletion. T cell lymphopenia following radiation exposure increases the risk of opportunistic infections. Currently, therapeutic options for promoting T cell recovery are not available. Interleukin-7 (IL-7) is a critical cytokine involved in the adaptive immune system. Previous murine and human studies have demonstrated the beneficial effects of exogenous IL-7 on T cell recovery and function. However, its clinical application has not been realized, at least partially due to its short half-life in circulation. In the current study, we examined the effect of NT-I7, a novel and long-acting human IL-7 molecule, in facilitating T cell reconstitution following TBI. C57BL/6 mice were first exposed to 5 Gy of TBI. After irradiation, mice received a weekly dose of NT-I7 subcutaneously at a dose of 10 mg/kg until day +21 (24 hr, day +7, +14, +21). T cell recovery was monitored in peripheral blood by flow cytometry. TBI rapidly depleted both CD4+ and CD8+ T cells. In the vehicle control group, it took at least 8 weeks for the T cells to recover back to the baseline levels. In contrast, CD4+ and CD8+ T cell counts recovered back to normal in 2 and 3 weeks respectively in NT-I7 treated mice. NT-I7 increased all T cell subsets including naïve, central and effector memory T cells. NT-I7 efficacy was similar when the treatment was initiated at day +7, when both CD4+ and CD8+ T cell counts were at the nadir. In addition, similar results were observed in mice irradiated with 2 and 7 Gy and in older animals. Using a novel T cell-specific luciferase reporter mouse strain, we further demonstrated that NT-I7 significantly enhanced systemic T cell recovery after TBI. The positive effect of NT-I7 on systemic T cell reconstitution was further confirmed by measuring T cell recovery in spleen and bone marrow directly. The positive effect of NT-I7 on T cell reconstitution post-TBI is a result of enhanced thymopoiesis because NT-I7 increased the number of both CD4+ and CD8+ recent thymic emigrants (Qa2+CD24+) in peripheral blood. More importantly, the numbers of total thymocytes and all thymocyte subsets including DN, DP, SP4, and SP8 were higher in the NT-I7 group compared with the vehicle control group when measured at day +21. Enhanced thymopoiesis is likely due to increased production of common lymphoid progenitors in the bone marrow since both the frequency and total number of common lymphoid progenitors