CD4 ؉ CD25 ؉ regulatory T cells are essential in the protection from organ-specific autoimmune diseases. In the pancreas, they inhibit actions of autoreactive T cells and thereby prevent diabetes progression. The signals that control the generation, the maintenance, or the expansion of regulatory T cell pool in vivo remain poorly understood. Here we show that a transient pulse of transforming growth factor  (TGF-) in the islets during the priming phase of diabetes is sufficient to inhibit disease onset by promoting the expansion of intraislet CD4 ؉ CD25 ؉ T cell pool. Approximately 40 -50% of intraislet CD4 ؉ T cells expressed the CD25 marker and exhibited characteristics of regulatory T cells including small size, high level of intracellular CTLA-4, expression of Foxp3, and transfer of protection against diabetes. Results from in vivo incorporation of BrdUrd revealed that the generation of a high frequency of regulatory T cells in the islets is due to in situ expansion upon TGF- expression. Thus, these findings demonstrate a previously uncharacterized mechanism by which TGF- inhibits autoimmune diseases via regulation of the size of the CD4 ؉ CD25 ؉ regulatory T cell pool in vivo.T ype I diabetes is an autoimmune disease that results from the failure of tolerance to beta-cell antigens (1). The mechanisms that have evolved to ensure discrimination between self and nonself are highly complex and not foolproof. Models of passive tolerance, such as thymic deletion of autoreactive T cells or nonreponsiveness in the periphery because of anergy or ignorance, cannot account for the presence of autoreactive T cells in healthy individuals despite the absence of the development of organ-specific autoimmune diseases. T cells endowed with suppressive function to control actions of autoreactive T cells were described decades ago and were thought originally to be a specialized T cell population the effect of which would be mediated by secreted antigen-specific factors (2). Nowadays, suppressor T cells (also referred to as regulatory T cells) are delineated into two cell subsets of natural regulatory (CD4 ϩ CD25 ϩ ) cells that emerge from the thymus (3, 4) and adaptive regulatory (CD4 ϩ CD25 Ϫ ) cells induced in the periphery to develop suppressive activity (5-7). However, this concept of dichotomous thymic CD25 ϩ versus adaptive CD25 Ϫ regulatory T cells has been challenged by several reports, supporting evidence for the peripheral generation of CD25 ϩ regulatory T cells in vivo and in vitro (8)(9)(10)(11)(12). The finding that suppressive functions are instructively programmed by the expression of Foxp3 finally provided the basis for integrating a unified model of regulatory T cell diversity (13-15). Forced expression of Foxp3 in CD4 ϩ CD25 Ϫ nonregulatory T cells, either by retroviral expression or in transgenic mice, showed acquisition of suppressive activity in vitro and inhibition of disease in vivo, inducing in a substantial proportion of Foxp3-bearing cells the expression of CD25 and GITR markers indicating that ex...
We report here that islet-specific expression of TNF-α can play a dual role in autoimmune diabetes, depending on its precise timing in relation to the ongoing autoimmune process. In a transgenic model (rat insulin promoter-lymphocytic choriomeningitis virus) of virally induced diabetes, TNF-α enhanced disease incidence when induced through an islet-specific tetracycline-dependent promoter system early during pathogenesis. Blockade of TNF-α during this phase prevented diabetes completely, suggesting its pathogenetic importance early in disease development. In contrast, TNF-α expression abrogated the autoimmune process when induced late, which was associated with a reduction of autoreactive CD8 lymphocytes in islets and their lytic activities. Thus, the fine-tuned kinetics of an autoreactive process undergo distinct stages that respond in a differential way to the presence of TNF-α. This observation has importance for understanding the complex role of inflammatory cytokines in autoimmunity.
Fas (Tnfrsf6, Apo-1, CD95) is a death receptor involved in apoptosis induced in many cell types. Fas have been shown to be expressed by insulin-producing beta cells in mice and humans. However, the importance of Fas in the development of autoimmune diabetes remains controversial. To further evaluate the importance of Fas in pathogenesis of diabetes, we generated NOD mice (nonobese diabetic mice developing spontaneous autoimmune diabetes) with beta cell-specific expression of a dominant-negative point mutation in a death domain of Fas, known as lpr cg or Fas cg . Spontaneous diabetes was significantly delayed in NOD mice expressing Fas cg , and the effect depended on the expression level of the transgene. However, Fas cg -bearing mice were still sensitive to diabetes transferred by splenocytes from overtly diabetic NOD mice. At the same time, Fas cg expression did neutralize the accelerating effect of transgenic Fas-ligand expressed by the same beta cells. Thus, both Fas-dependent and -independent mechanisms are involved in beta cell destruction, but interference with the Fas pathway early in disease development may retard or prevent diabetes progression.
Background Patients presenting to thoracic surgeons with pulmonary nodules suspicious for lung cancer have varied diagnostic options including navigation bronchoscopy (NB), computed tomography fine needle aspiration (CT-FNA), 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET) and video assisted thoracic surgery (VATS). We studied the relative cost-effective initial diagnostic strategy for a 1.5-2 cm nodule suspicious for cancer. Methods A decision analysis model was developed to assess the costs and outcomes of four initial diagnostic strategies for diagnosis of a 1.5-2 cm nodule with either a 50% or 65% pretest probability of cancer. Medicare reimbursement rates were used for costs. Quality adjusted life years were estimated using patient survival based on pathologic staging and utilities derived from the literature. Results When cancer prevalence was 65%, tissue acquisition strategies of NB and CT-FNA had higher quality adjusted life years compared to either FDG-PET or VATS and VATS was the most costly strategy. In sensitivity analyses NB and CT-FNA were more cost-effective than FDG-PET when FDG-PET specificity was less than 72%. NB, CT-FNA, and FDG-PET had similar cost effectiveness when cancer prevalence was 50%. Conclusions NB and CT-FNA diagnostic strategies are more cost-effective than either VATS biopsy or FDG-PET scan to diagnose lung cancer in moderate to high-risk nodules and resulted in fewer nontherapeutic operations when FDG-PET specificity was less than 72%. FDG-PET scan for diagnosis of lung cancer may not be cost-effective in regions of the country where specificity is low.
Neonatal islet-specific expression of tumor necrosis factor (TNF)-α in nonobese diabetic mice promotes diabetes by provoking islet-infiltrating antigen-presenting cells to present islet peptides to autoreactive T cells. Here we show that TNF-α promotes autoaggression of both effector CD4+ and CD8+ T cells. Whereas CD8+ T cells are critical for diabetes progression, CD4+ T cells play a lesser role. TNF-α–mediated diabetes development was not dependent on CD154–CD40 signals or activated CD4+ T cells. Instead, it appears that TNF-α can promote cross-presentation of islet antigen to CD8+ T cells using a unique CD40–CD154-independent pathway. These data provide new insights into the mechanisms by which inflammatory stimuli can bypass CD154–CD40 immune regulatory signals and cause activation of autoreactive T cells.
Foxp3 ؉ regulatory T cells develop in the thymus and are essential for maintaining peripheral tolerance to self tissues. We report the critical requirement for CD154 up-regulation specifically on, and during the thymic development of, Foxp3 ؉ regulatory T cells for the induction of their clonal expansion within the medulla. In the absence of this signal, there was a severe reduction in their thymic generation and output, leading to decreased peripheral numbers. Importantly, CD40 expression on either thymic dendritic or epithelial cells was sufficient to promote the development of normal numbers of Foxp3 ؉ regulatory T cells. This work suggests that CD154-transduced signals promote Foxp3 ؉ regulatory T cell development and highlights the plasticity of the thymic stroma for supporting their generation. Crucially, this study demonstrates that Foxp3 ؉ regulatory T cells can promiscuously accept a single critical signal necessary for their thymic development from different cellular sources, redefining our understanding of their generation.CD154 ͉ thymus ͉ thymic epithelial cells ͉ CD40 R egulatory T cells (Tregs) actively suppress autoreactive T cells, thereby limiting aberrant immune responses and maintaining tolerance toward self tissues (1). Deficiencies in this T cell subset in humans and mice can lead to severe autoimmunity. Initially, these suppressor cells were identified as CD4 ϩ CD25 ϩ T cells (2), a phenotype that also included activated CD4 ϩ T cells, but, recently, Foxp3 has been characterized as the master regulator of their development and function (3-5) and is used as a highly specific marker for Tregs (6). Foxp3 ϩ Tregs develop in the thymus as part of the normal T cell ontogeny processes (7), and Foxp3 expression is largely restricted to the thymic medulla and CD4 ϩ CD8 Ϫ (CD4SP) thymocyte subset; the end stage of CD4 ϩ T cell development. Thymic output of Foxp3 ϩ Tregs is temporally delayed (8), and their development requires a highaffinity self-reactive T cell receptor (9, 10), the costimulatory molecule CD28 (11), and possibly IL-2 (12). It has been suggested that medullary thymic epithelial cells (mTECs), which express and present tissue-specific antigens (TSAs) on MHC class II (MHC II) molecules, drive Foxp3 ϩ Treg selection (13). Similarly, dendritic cells (DCs) are thought to induce CD4 ϩ CD25 ϩ Tregs in the human thymus through a T cell antigen receptor (TCR)-peptide-MHC II interaction (14). However, the relative contributions of thymic dendritic and epithelial cells in promoting and supporting the development of a polyclonal Foxp3 ϩ Treg repertoire are not clear. In addition, the cellular origin and temporal importance of the signals necessary for Foxp3 ϩ Treg development have not been determined, and, therefore, the rules governing how developing Foxp3 ϩ Tregs receive and process these signals are poorly understood.We report that the CD40-CD154 pathway is critical for promoting the thymic development of Foxp3 ϩ Tregs. CD154 up-regulation specifically on developing Foxp3 ϩ Tregs promoted the...
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