CD4+Foxp3+ regulatory T cells (Tregs) play an essential role in immune tolerance, acting to suppress autoreactive T cells that escape negative selection during thymic development. Inactivating mutations in the Foxp3 gene, the lineage-specifying transcription factor for Tregs, cause fatal multi-organ autoimmunity in mice and humans. Research in patients and animal models has implicated numerical or functional deficits in Tregs as a contributing factor in many prevalent autoimmune diseases such as type 1 diabetes, systemic lupus erythematosus, and rheumatoid arthritis. Treg dysfunction is also crucial to the breakdown of tolerance in the setting of graft-versus-host disease (GvHD), a common and potentially fatal immune reaction of donor T cells against recipient tissues following hematopoietic stem cell transplantation. Because Treg defects are involved in the pathogenesis of diverse autoimmune and alloimmune disorders, immunomodulatory agents capable of enhancing Treg proliferation and suppressive activity have attracted considerable therapeutic interest. The cytokine interleukin-2 (IL-2) has emerged as the agent most central to this investigation. Tregs characteristically express high levels of the IL-2 receptor ?-chain (CD25), allowing them to respond to much lower concentrations of IL-2 than other T cell lineages. A large body of evidence from in vitro studies, animal models, and early human trials has established that administering IL-2 at low doses can induce selective proliferation and activation of the Treg compartment, with promising clinical benefits. However, critical parameters of this therapy such as dose-response relationship, administration schedule, and treatment duration remain unresolved. Realizing the full potential of this treatment will require improvements in our knowledge of how IL-2 influences the biology of mature Tregs. To gather data on this question directly, this study relies upon the innovative approach of a CD25 conditional knockout that is tamoxifen-inducible and specific for Foxp3- expressing cells. Utilizing this efficient, Treg-targeted mechanism to disrupt IL-2 receptor function at a predetermined point in time, it will be possible to gain novel insights into the impact of constitutive IL-2 signals on the homeostatic maintenance, lineage stability, and activation status of mature Tregs in the periphery. We hypothesize that, following abrogation of IL-2R signaling, the mature Tregs of C57BL/6 mice will show a diminished capacity to sustain their numbers through homeostatic proliferation, reduced fidelity of Foxp3 expression, and a reduced ability to differentiate into highly activated, effector-like cellular phenotypes. Clarifying the role of IL-2in these processes will have numerous applications in the ongoing effort to develop IL-2 therapy as a safe and effective strategy for clinical immunosuppression.
Naturally occurring Foxp3+ regulatory T cells (Tregs) play an indispensable role in sustaining immune tolerance, and it has been discovered that interleukin-2 (IL-2) administered at low doses can selectively activate and expand this cell population. However, numerous uncertainties surrounding the influence of IL-2 on mature Tregs jeopardize this promising new tool for the treatment of autoimmune disease. This study aims to resolve these questions by directly examining the importance of IL-2 signaling as a determinant of Treg survival, stability, and function.
| Toomer, Kevin H; Malek, Thomas R (2018) Cytokine Signaling in the Development and Homeostasis of Regulatory T cells. Cold Spring Harb Perspect Biol 10: |
| Toomer, Kevin H; Yuan, Xiaomei; Yang, Jing et al. (2016) Developmental Progression and Interrelationship of Central and Effector Regulatory T Cell Subsets. J Immunol 196:3665-76 |
