Targeting IL-15 to CD8 Treg results in their selective expansion and activation and is a potential therapeutic approach to ameliorate autoimmune disease in patients with deficient CD8 Treg populations 4856

Abstract Description CD8 regulatory T cells (CD8 Treg) are characterized by their capacity to kill self-reactive and pathogenic CD4 T cells. Control of pathogenic CD4 T cells appears impaired in autoimmune disease, in part due to reduced CD8 Treg prevalence and function. We developed an IL-15 mutein with reduced potency tethered to a targeting antibody to promote selective expansion, activation, and cytolytic capacity of CD8 Treg, with the potential of ameliorating disease. Here we demonstrate by flow cytometry and differential gene expression that the targeted IL-15 mutein selectively increased expansion and activation of CD8 Treg, while other common gamma chain cytokines did not show this effect. Targeted IL-15 mutein induced selective signaling in CD8 Treg in a pSTAT5 flow cytometry assay using PBMC from healthy donors and SLE patients. Targeted IL-15 mutein also selectively expanded and increased the prevalence of CD8 Treg in healthy donors while maintaining CD8 Treg TCR clonality. Using immunocompetent and humanized acute graft versus host disease mouse models, we observed selective binding, activation, and expansion of CD8 Treg. A decrease of CD4 T cells was also observed, consistent with CD8 Treg activation and their proposed mechanism of action. We propose that the selective IL-15 mediated expansion of CD8 Treg may have therapeutic potential in autoimmune diseases that are characterized by a reduced prevalence of CD8 Treg. Topic Categories Therapeutic Approaches to Autoimmunity (THER)