No abstract

Diabetes imposes a large economic burden on health care systems across the world, yet varies across world regions. Diabetes prevention and effective management of diabetes should be a public health priority to reduce the financial burden.

Condensins are ubiquitously expressed multiprotein complexes that are important for chromosome condensation and epigenetic regulation of gene transcription, but whose specific roles in vertebrates are poorly understood. We describe a mouse strain, nessy, isolated during an ethylnitrosourea screen for recessive immunological mutations. The nessy mouse has a defect in T lymphocyte development that decreases circulating T cell numbers, increases their expression of the activation/memory marker CD44, and dramatically decreases the numbers of CD4 ؉ CD8 ؉ thymocytes and their immediate DN4 precursors. A missense mutation in an unusual alternatively spliced first exon of the kleisin ␤ gene, a member of the condensin II complex, was shown to be responsible and act in a T cell-autonomous manner. Despite the ubiquitous expression and role of condensins, kleisin ␤ nes/nes mice were viable, fertile, and showed no defects even in the parallel pathway of B cell lymphocyte differentiation. These data define a unique lineage-specific requirement for kleisin ␤ in mammalian T cell differentiation.Ncaph2 ͉ splice variation

Foxp3 ؉ regulatory T cells play a pivotal role in maintaining self-tolerance and immune homeostasis. In the absence of regulatory T cells, generalized immune activation and multiorgan T cell-driven pathology occurs. Although the phenomenon of immunologic control by Foxp3 ؉ regulatory T cells is well recognized, the comparative effect over different arms of the immune system has not been thoroughly investigated. Here, we generated a cohort of mice with a continuum of regulatory T-cell frequencies ranging from physiologic levels to complete deficiency. This titration of regulatory T-cell depletion was used to determine how different effector subsets are controlled. We found that in vivo Foxp3 ؉ regulatory T-cell frequency had a proportionate relationship with generalized T-cell activation and Th1 magnitude, but it had a surprising disproportionate relationship with Th2 magnitude. The asymmetric regulation was associated with efficient suppression of Th2 cells through additional regulations on the apoptosis rate in Th2 cells and not Th1 cells and could be replicated by CTLA4-Ig or anti-IL-2 Ab. These results indicate that the Th2 arm of the immune system is under tighter control by regulatory T cells than the Th1 arm, suggesting that Th2-driven diseases may be more responsive to regulatory T-cell manipulation. (Blood. 2011;118(7):1845-1853) IntroductionFoxp3 ϩ Regulatory T cells (Tregs) are a key modulator of immune system activation, with the ability to suppress the proliferation and cytokine production of CD4 ϩ and CD8 ϩ T cells. [1][2][3] Although Tregs require Ag-specific stimulation for activation, after activation the suppressive function acquired is Ag nonspecific. 4 This allows Tregs to act as a nonspecific rheostat on immune activation, decreasing the rate of spontaneous effector T-cell activation and thereby increasing dependence on pathogen-associated danger stimuli. 5 As such, Tregs not only prevent autoimmunity because of autoreactive T cells 6 but also reduce the activity of beneficial antipathogen 7 and antitumor 8 responses.The model of Tregs as indiscriminate suppressors is being challenged by data showing surprisingly sophisticated molecular underpinning of Treg suppression. Foxp3 ϩ Tregs use different molecular strategies to suppress T cells in different anatomical locations and to control different effector subpopulations. 9-14 On the receiving end of immune tolerance, there is a growing body of evidence that Th1 and Th2 cells have qualitative differences in sensitivity to intrinsic regulation. For example, Th1 cells have enhanced, and more rapid, activation-induced cell death (AICD). 15 In Th1 cells, AICD is mediated by Fas-FasL signaling and regulated by CD44, 16,17 whereas in Th2 cells AICD is mediated by granzyme B activity and regulated by VIP. 18,19 Likewise, Th1 cells are sensitive to endogenous galectin 1-induced cell death, whereas Th2 cells are resistant because of differential sialylation. 20 Because Treg cells have been reported to use both granzyme B and galectin 1 as regulatory med...