Objective
Treg cells express the transcription factor, forkhead box P3 (FOXP3), to maintain their suppressive function. As FOXP3 loss results in dysfunctional Treg cells and therapeutic failure in autoimmunity and transplantation, we studied the mechanisms that control FOXP3 expression in human Treg cells and found that IL-37 plays an important role in human Treg cells. Therefore, in this grant proposal, we will examine the role of IL-37 expression in Treg cells of T1D using animal models (Aim 1) and T1D patient blood samples (Aim 2).
Background Rationale
Immune tolerance is critical for suppressing autoimmunity, allergic reactions, and immune rejection. Evidence supports that type 1 diabetes (T1D) is caused by an immune-mediated attack of pancreatic beta cells and that an inappropriate balance between autoreactive T cells and regulatory T (Treg) cells impairs peripheral tolerance. Therefore, one of the therapeutic strategies of T1D is to enhance the number and functionality of Treg cells ex vivo and in situ. However, to date, clinical trials using an adoptive Treg infusion have shown insufficient persistency of Treg cells as well as expansion of undesired cytotoxic cells. While novel genome editing techniques, identification of stable Treg markers, and addition of Treg-supportive cytokines in vivo have improved the efficacy and expansion of primary Treg cells, translating the valuable findings into effective therapeutics has still proven challenging. These modified Treg cells may not be robust, persistent enough, or may not be antigen-specific. Further optimization or modification is needed to make effective therapeutics.
Description of Project
Immune tolerance is critical for suppressing autoimmunity, allergic reactions, and immune rejection. Evidence supports that type 1 diabetes (T1D) is caused by an immune-mediated attack of pancreatic beta cells and that an inappropriate balance between autoreactive T cells and regulatory T (Treg) cells impairs peripheral tolerance. Therefore, one of the therapeutic strategies of T1D is to enhance the number and functionality of Treg cells ex vivo and in situ. However, to date, clinical trials using an adoptive Treg infusion have shown insufficient persistency of Treg cells as well as expansion of undesired cytotoxic cells. While novel genome editing techniques, identification of stable Treg markers, and addition of Treg-supportive cytokines in vivo have improved the efficacy and expansion of primary Treg cells, translating the valuable findings into effective therapeutics has still proven challenging. These modified Treg cells may not be robust, persistent enough, or may not be antigen-specific. Further optimization or modification is needed to make effective therapeutics. Treg cells express the transcription factor, forkhead box P3 (FOXP3), to maintain their suppressive function. As FOXP3 loss results in dysfunctional Treg cells and therapeutic failure in autoimmunity and transplantation, we studied the mechanisms that control FOXP3 expression in human Treg cells and found that IL-37 plays an important role in human Treg cells. Therefore, in this grant proposal, we will examine the role of IL-37 expression in Treg cells of T1D using animal models (Aim 1) and T1D patient blood samples (Aim 2). In Aim 1, we anticipate defining the IL-37 effects in Treg cells in a NOD T1D mouse model. In Aim 2, we anticipate understanding the phenotypes and functions of human Treg cells related to IL-37 in new-onset T1D patients. While the IL37 gene is not present in mice, human IL-37 is compatible with mouse molecules and can be assessed in mice; thus, IL-37 improves the functions of mouse Treg cells. Nevertheless, this cytokine has not been examined in T1D. The proposal is significant as it addresses the current clinical challenge of adoptive Treg therapy in T1D.
Anticipated Outcome
In Aim 1, we anticipate defining the IL-37 effects in Treg cells in a NOD T1D mouse model
In Aim 2, we anticipate understanding the phenotypes and functions of human Treg cells related to IL-37 in new-onset T1D patients.
Relevance to T1D
While the IL37 gene is not present in mice, human IL-37 is compatible with mouse molecules and can be assessed in mice; thus, IL-37 improves the functions of mouse Treg cells. Nevertheless, this cytokine has not been examined in T1D. The proposal is significant as it addresses the current clinical challenge of adoptive Treg therapy in T1D.