Type 1 diabetes(T1D) is an autoimmune disease that results from the destruction of insulin-producing cells by autoreactive T cells,leading to lifelong dependency on insulin therapy and increased risk of long-term card...Type 1 diabetes(T1D) is an autoimmune disease that results from the destruction of insulin-producing cells by autoreactive T cells,leading to lifelong dependency on insulin therapy and increased risk of long-term cardiovascular complications.Here we take the opportunity of the 20thanniversary of the generation of the BDC2.5 TCR transgenic non-obese diabetic(NOD) mouse model,to provide a brief overview of the significant progress that has been made in understanding the role of T cells in the disease pathogenesis period.This included development of hundreds of reagents that block or even reverse new-onset disease by directly or indirectly controlling T cells.We also reflect on the sobering fact that none of these strategies has shown significant efficacy in clinical trials and discuss potential reasons hindering translation of the preclinical findings into successful therapeutic strategies and potential ways forward.展开更多
Interleukin-15 (IL-15) is essential for the survival of memory CD8^+ and CD4^+ T cell subsets, and natural killer and natural killer T cells. Here, we describe a hitherto unreported role of IL-15 in regulating hom...Interleukin-15 (IL-15) is essential for the survival of memory CD8^+ and CD4^+ T cell subsets, and natural killer and natural killer T cells. Here, we describe a hitherto unreported role of IL-15 in regulating homoeostasis of naive CD4^+ T cells. Adoptive transfer of splenocytes from non-obese diabetic (NOD) mice results in increased homeostatic expansion of T cells in lymphopenic NOD.scid.II15^-/- mice when compared to NOD.scid recipients. The increased accumulation of CD4^+ T cells is also observed in NOD.II15^-/- mice, indicating that IL-15-dependent regulation also occurs in the absence of lymphopenia. NOD.scid mice lacking the I L- 15Ra chain, but not those lacking the common gamma chain, also show increased accumulation of CD4^+ T cells. These findings indicate that the IL-15-mediated regulation occurs directly on CD4^+ T cells and requires trans-presentation of IL-15. CD4^+ T cells expanding in the absence of IL-15 signaling do not acquire the characteristics of classical regulatory T cells. Rather, CD4^+ T cells expanding in the absence of IL-15 show impaired antigen-induced activation and IFN-7 production. Based on these findings, we propose that the IL-15-dependent regulation of the naive CD4^+ T-cell compartment may represent an additional layer of control to thwart potentially autoreactive cells that escape central tolerance, while permitting the expansion of memory T cells.展开更多
基金Supported by The NIH(1R56AI099027 and 1R01AI099027-01)American Heart Association(10GRNT4200003)
文摘Type 1 diabetes(T1D) is an autoimmune disease that results from the destruction of insulin-producing cells by autoreactive T cells,leading to lifelong dependency on insulin therapy and increased risk of long-term cardiovascular complications.Here we take the opportunity of the 20thanniversary of the generation of the BDC2.5 TCR transgenic non-obese diabetic(NOD) mouse model,to provide a brief overview of the significant progress that has been made in understanding the role of T cells in the disease pathogenesis period.This included development of hundreds of reagents that block or even reverse new-onset disease by directly or indirectly controlling T cells.We also reflect on the sobering fact that none of these strategies has shown significant efficacy in clinical trials and discuss potential reasons hindering translation of the preclinical findings into successful therapeutic strategies and potential ways forward.
文摘Interleukin-15 (IL-15) is essential for the survival of memory CD8^+ and CD4^+ T cell subsets, and natural killer and natural killer T cells. Here, we describe a hitherto unreported role of IL-15 in regulating homoeostasis of naive CD4^+ T cells. Adoptive transfer of splenocytes from non-obese diabetic (NOD) mice results in increased homeostatic expansion of T cells in lymphopenic NOD.scid.II15^-/- mice when compared to NOD.scid recipients. The increased accumulation of CD4^+ T cells is also observed in NOD.II15^-/- mice, indicating that IL-15-dependent regulation also occurs in the absence of lymphopenia. NOD.scid mice lacking the I L- 15Ra chain, but not those lacking the common gamma chain, also show increased accumulation of CD4^+ T cells. These findings indicate that the IL-15-mediated regulation occurs directly on CD4^+ T cells and requires trans-presentation of IL-15. CD4^+ T cells expanding in the absence of IL-15 signaling do not acquire the characteristics of classical regulatory T cells. Rather, CD4^+ T cells expanding in the absence of IL-15 show impaired antigen-induced activation and IFN-7 production. Based on these findings, we propose that the IL-15-dependent regulation of the naive CD4^+ T-cell compartment may represent an additional layer of control to thwart potentially autoreactive cells that escape central tolerance, while permitting the expansion of memory T cells.