ABSTRACT
TNF/CD80 mice, a CD8(+) T cell-mediated model for type 1 diabetes, transgenically express tumor necrosis factor alpha (TNF-alpha) and the costimulatory molecule CD80 in their pancreatic islets. Here we show that these molecules bypass the need for CD40-CD154 costimulatory interactions in activation of CD8(+) T cells, allowing us to determine the role of CD40-CD154 signals in regulation of autoaggressive CD8(+) T cells after their in vivo priming. TNF/CD80 CD154-deficient mice rapidly develop diabetes, whereas CD154-sufficient mice do not. This finding correlates with the decreased numbers of CD4(+)CD25(+) T regulatory (T(R)) cells in the islets and pancreatic lymph nodes, in comparison to disease-protected CD154-sufficient mice. Administration of a CD40 agonistic antibody induces a systemic and tissue-specific increase in T(R) cells. However, this increase fails to delay diabetes development in the absence of CD154. Adoptive transfer studies show that CD8(+) T cells from TNF/CD80 CD154-deficient, but not CD154-sufficient, mice are resistant to regulation in vivo. This study provides evidence that CD40-transduced signals initiate T(R) cell increase in vivo and that CD154-transduced signals sensitize autoaggressive CD8(+) T cells to suppression.
Subject(s)
CD40 Ligand/genetics , CD40 Ligand/immunology , CD8-Positive T-Lymphocytes/immunology , Diabetes Mellitus, Type 1/immunology , Animals , CD40 Antigens/immunology , Diabetes Mellitus, Type 1/genetics , Disease Models, Animal , Flow Cytometry , Islets of Langerhans/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , RNA, Messenger/geneticsABSTRACT
Pancreatic lymph node-derived CD4+CD25+ T regulatory (Treg) cells inhibit in situ differentiation of islet-reactive CD8+ T cells into cytotoxic T lymphocytes, thereby preventing diabetes progression. The mechanism by which these Treg cells suppress anti-islet CD8+ T cells is unknown. Here, we show by using a CD8+ T cell-mediated model of type 1 diabetes that transforming growth factor (TGF)-beta-TGF-beta receptor signals are critical for CD4+CD25+ Treg cell regulation of autoreactive islet-specific cytotoxic T lymphocytes. Transgenic expression of tumor necrosis factor alpha from birth to 25 days of age in the islets of B6 mice that constitutively express CD80 on their beta cells results in accumulation of CD4+CD25+TGF-beta+ cells exclusively in the islets and pancreatic lymph nodes, which delays diabetes progression. In contrast, expression of tumor necrosis factor alpha until 28 days of age prevents islet accumulation of CD4+CD25+TGF-beta+ Treg cells, resulting in acceleration to diabetes. Furthermore, adoptive transfer experiments demonstrated that CD4+CD25+ Treg cells could not control naïve or activated islet-reactive CD8+ T cells bearing a dominant negative TGF-beta receptor type II. Our data demonstrate that, in vivo, TGF-beta signaling in CD8+ T cells is critical for CD4+CD25+ Treg cell suppression of islet-reactive CD8+ T cells in type 1 diabetes.
