CD4+CD25+FOXP3+ regulatory T cells (Tregs) control the activation and expansion of alloreactive and autoreactive T cell clones. Because uncontrolled activation and expansion of autoreactive T cells occur in an IL-7–rich environment, we explored the possibility that IL-7 may affect the function of Treg. We show that the functional high-affinity IL-7R is expressed on both naive and memory Tregs, and exposure to IL-7 results in STAT-5 phosphorylation. Naive, but not memory, Tregs proliferated greatly and acquired a memory phenotype in the setting of a suppression assay when IL-7 was present. Importantly, the presence of IL-7 abrogated the capacity of Tregs to suppress proliferation of conventional T cells in response to TCR activators, including alloantigens and autoantigens. Removal of IL-7 restored the suppressive function of Tregs. Preblocking of the IL-7R on the Tregs also restored suppressor function, indicating that IL-7 directly affected Treg function. Thus, prolonged periods of homeostatic expansion can temporarily release natural regulatory brakes on T cells, thereby providing an additional mechanism for activating and expanding alloreactive and autoreactive T cells.
Objectives: Despite the well-defined histological types of non-small cell lung cancer (NSCLC), a given stage is often associated with wide-ranging survival rates and treatment outcomes. This disparity has led to an increased demand for the discovery and identification of new informative biomarkers. Methods: In the current study, we screened 81 NSCLC samples using Illumina® whole-genome gene expression microarrays in an effort to identify differentially expressed genes and new NSCLC biomarkers. Results: We identified novel genes whose expression was upregulated in NSCLC, including SPAG5, POLH, KIF23, and RAD54L, which are associated with mitotic spindle formation, DNA repair, chromosome segregation, and dsDNA break repair, respectively. We also identified several novel genes whose expression was downregulated in NSCLC, including SGCG, NLRC4, MMRN1, and SFTPD, which are involved in extracellular matrix formation, apoptosis, blood vessel leakage, and inflammation, respectively. We found a significant correlation between RNA degradation and survival in adenocarcinoma cases. Conclusions: Even though the follow-up time was too limited to draw final conclusions, we were able to show better prediction p values in a group selection based on molecular profiles compared to histology. The current study also uncovered new candidate biomarker genes that are likely to be involved in diverse processes associated with NSCLC development.
Cure of type 1 diabetes (T1D) by immune intervention at disease onset depends on the restoration of insulin secretion by endogenous b-cells. However, little is known about the potential of b-cell mass and function to recover after autoimmune attack ablation. Using a longitudinal in vivo imaging approach, we show how functional status and mass of b-cells adapt in response to the onset and remission of T1D. We demonstrate that infiltration reduces b-cell mass prior to onset and, together with emerging hyperglycemia, affects b-cell function. After immune intervention, persisting hyperglycemia prevents functional recovery but promotes b-cell mass increase in mouse islets. When blood glucose levels return to normoglycemia b-cell mass expansion stops, and subsequently glucose tolerance recovers in combination with b-cell function. Similar to mouse islets, human islets exhibit cell exhaustion and recovery in response to transient hyperglycemia. However, the effect of hyperglycemia on human islet mass increase is minor and transient. Our data demonstrate a major role of functional exhaustion and recovery of b-cells during T1D onset and remission. Therefore, these findings support early intervention therapy for individuals with T1D.Successful therapy at the onset of type 1 diabetes (T1D) not only requires an effective block of the pathological autoimmune process, but also the restoration of adequate insulin levels. Most promising for optimal glucose control is endogenous b-cell activity, which even at low levels reduces the risk for complications and hypoglycemic events (1). Therefore, preserved b-cell function and mass at diagnosis and their potential to recover after immune intervention are a crucial aspect of T1D therapy. Initially, b-cell mass was suggested to be almost completely destroyed at T1D onset (2,3), which questioned the justification of immune intervention at this late time point (4). However, more recent data demonstrate preserved b-cell mass and function in patients with newly diagnosed (5-7) and long-standing T1D (8,9). These observations raise the question of whether immune intervention at T1D onset will allow functional and morphological recovery of the residual b-cells. Indications of a potential recovery are the so-called "honeymoon phase" observed after initial insulin treatment (10), as well as the reported detection of b-cell proliferation in patients with T1D (11). However, it is unclear if b-cell mass and function have the capability to recover after immune intervention, and their distinct roles in the remission process have not been shown.Here we take advantage of a noninvasive in vivo imaging platform (12,13), and the possibility of successful immune intervention in mouse models of T1D (14), to study functional and morphological changes of b-cells and islets during the onset and remission of T1D. Our results demonstrate substantial morphological and functional b-cell plasticity before and after immune intervention. We furthermore show that b-cell mass and function differentially progress duri...
Under physiological conditions, studies on the biology of naturally inducedAdditional supporting information may be found in the online version of this article at the publisher's web-site
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