No abstract

TNF͞CD80 mice, a CD8 ؉ T cell-mediated model for type 1 diabetes, transgenically express tumor necrosis factor ␣ (TNF-␣) 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. TNF͞CD80 CD154-deficient mice rapidly develop diabetes, whereas CD154-sufficient mice do not. This finding correlates with the decreased numbers of CD4 ؉ CD25 ؉ T regulatory (TR) 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 TNF͞CD80 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.T he deletion of self-reactive T cells by thymic negative selection is not complete, leading to release of cells with autoimmune potential into the periphery (1). Type 1 diabetes (T1D) is an autoimmune disease in which lymphocytic infiltration of the islets of Langerhans, a process termed insulitis, is followed by T cell-mediated destruction of the insulin-producing beta cells of the pancreas (2).It has been demonstrated by in vivo depletion studies that beta cell destruction, in mouse models of T1D, is mediated by CD8 Because of this critical role for CD40-CD154 signals in the priming phase of immune responses, investigations have centered on ablation of this pathway for the prevention of autoimmune disease (9-11) and transplant rejection (12)(13)(14).Inflammation resulting from viral infections has long been associated with development of autoimmunity (15). In particular, the proinflammatory cytokine tumor necrosis factor ␣ (TNF-␣) plays an important role in the pathogenesis of several autoimmune diseases, including T1D. CD40-CD154 blockade or CD154 deficiency in nonobese diabetic (NOD) mice prevents insulitis and T1D (10). However, this protection can be overcome by systemic administration, or constitutive islet-specific expression of TNF-␣ from a rat insulin promoter (RIP-TNF-␣) (16,17). The presence of TNF-␣ bypasses the requirement for CD40-CD154 interactions in priming and differentiation of islet-specific CD8 ϩ T cells in CD154-deficient RIP-TNF-␣ NOD mice (18).Recently, a unique population of thymic-derived T regulatory (T R ) cells has been identified and shown to suppress activation of autoreactive T cells (19,20). Phenotypic characterization of T R cells includes expression of CD4, CD25 (21), and CTLassociated antigen 4 (22). T R cell development and function depend on the tran...