Tuesday, April 29, 2025
4/29/2025
Mechanisms of Il-2-mediated immune tolerance - PROJECT SUMMARY Foxp3+ regulatory T cells (TR) are essential for establishing and maintaining immune tolerance, and manipulating TR activity is an attractive new therapeutic strategy for treating autoimmune and inflammatory diseases. The development, homeostasis and function of TR depends on the cytokine IL-2, and TR constitutively express the high affinity IL-2 receptor which allows them to compete for limiting IL-2 produced by activated CD4+ T cells. As a strategy for increasing TR abundance and function to treat autoimmune disease, we have developed a novel IL-2 ‘mutein’ that is highly TR selective, potently expands TR in vivo, and arrests ongoing autoimmunity and induces durable disease protection in NOD mice. Interestingly, we have shown that in both mice and humans, IL-2 mutien treatment is associated with pronounced expansion of a subset of highly activated TR characterized by expression of activation markers associated with T cell receptor stimulation. Furthermore, expanded TR express high levels of the immunosuppressive molecule CTLA4, and IL-2 mutein treatment inhibits the activation of dendritic cells (DCs) and their surface expression of the key co-stimulatory ligands CD80 and CD86 that are required for full effector T cell activation. Based on these results, we hypothesize that IL-2 mutein treatment promotes TR/DC interaction, and that this results in synergistic IL-2 and TCR signaling that drives the proliferation and expansion of highly activated TR that inhibit DC function and prevent the activation, differentiation and function of autoreactive T cells. In this proposal we use a number of innovative methods to test this hypothesis, and these experiments will provide a comprehensive mechanistic understanding of how IL-2 muteins function to promote TR expansion and induction of immune tolerance. This has important implications for the translation of IL-2 muteins into therapeutic use, and will provide important new insights in the basic biology of IL-2-mediated control of TR homeostasis and function.
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