Harnessing T Cell Generation and Metabolism to Modulate T Cell Recovery Following Radiation Exposure and Bone Marrow Transplantation

Abstract

Total body irradiation (TBI) causes profound suppression of hematopoiesis and T cell depletion, increasing chances of morbidity associated with opportunistic infections in the lymphopenic condition. Currently, therapeutic options for improving recovery of the T cell compartment following radiation exposure are not available. Although mouse and nonhuman primate studies have demonstrated prolonged effects of TBI on T cell reconstitution, there is a lack of understanding in the kinetics and metabolic signatures of radioresistant T cells actively undergoing homeostatic proliferation. Furthermore, whether kinetics of systemic T cell recovery recapitulates T cell recovery in circulation remains unknown. In the current study, we performed comprehensive immunophenotyping and single-cell sequencing analyses of radioresistant T cells, as well as imaging of T cell recovery in vivo, to determine preferentially upregulated pathways during T cell recovery. We identified T cell populations unique to TBI treatment that upregulate components essential to support oxidative phosphorylation, a mitochondria-dependent metabolic process. We further investigated mechanisms of recovery in donor T cells following TBI exposure in the bone marrow transplant setting. We demonstrated that recovery of alloreactive donor T cells was highly dependent on aerobic glycolysis, which can be manipulated to reduce graft-versus-host-disease and preserve the functional recovery of non-alloreactive donor T cells. We then examined the effect of NT-I7, a long-acting recombinant human IL-7, in mediating T cell reconstitution due to its role in integrating metabolic requirements with pathways critical for T cell survival and growth. We found that NT-I7 led to accelerated T cell recovery following TBI through both thymic-dependent and independent pathways. More importantly, NT-I7 promoted functional T cell recovery. Taken together, these findings reveal unique kinetics and mechanisms of T cell recovery in response to radiation. The study also identified NT-I7 as a potential therapeutic treatment during T cell lymphopenia by supporting critical mechanisms utilized in T cell recovery.