The final pathway of β cell destruction leading to insulin deficiency, hyperglycemia, and clinical type 1 diabetes is unknown. Here we show that circulating CTLs can kill β cells via recognition of a glucose-regulated epitope. First, we identified 2 naturally processed epitopes from the human preproinsulin signal peptide by elution from HLA-A2 (specifically, the protein encoded by the A*0201 allele) molecules. Processing of these was unconventional, requiring neither the proteasome nor transporter associated with processing (TAP). However, both epitopes were major targets for circulating effector CD8 + T cells from HLA-A2 + patients with type 1 diabetes. Moreover, cloned preproinsulin signal peptide-specific CD8 + T cells killed human β cells in vitro. Critically, at high glucose concentration, β cell presentation of preproinsulin signal epitope increased, as did CTL killing. This study provides direct evidence that autoreactive CTLs are present in the circulation of patients with type 1 diabetes and that they can kill human β cells. These results also identify a mechanism of self-antigen presentation that is under pathophysiological regulation and could expose insulin-producing β cells to increasing cytotoxicity at the later stages of the development of clinical diabetes. Our findings suggest that autoreactive CTLs are important targets for immune-based interventions in type 1 diabetes and argue for early, aggressive insulin therapy to preserve remaining β cells.

Successful solutions to pressing social ills tend to consist of innovative combinations of a limited set of alternative ways of perceiving and resolving the issues. These contending policy perspectives justify, represent and stem from four different ways of organizing social relations: hierarchy, individualism, egalitarianism and fatalism. Each of these perspectives: (1) distils certain elements of experience and wisdom that are missed by the others;(2) provides a clear expression of the way in which a signifi cant portion of the populace feels we should live with one another and with nature; and (3) needs all of the others in order to be sustainable. ' Clumsy solutions ' -policies that creatively combine all opposing perspectives on what the problems are and how they should be resolved -are therefore called for. We illustrate these claims for the issue of global warming.Most climatologists agree that by burning fossil fuels and engaging in other forms of consumption and production we are increasing the amount of greenhouse gases that fl oat around in the atmosphere. These gases, in trapping some of the sun ' s heat, warm the earth and enable life. The trouble is,

Human memory B cells and marginal zone (MZ) B cells share common features such as the expression of CD27 and somatic mutations in their IGHV and BCL6 genes, but the relationship between them is controversial. Here, we show phenotypic progression within lymphoid tissues as MZ B cells emerge from the mature naïve B cell pool via a precursor CD27−CD45RBMEM55+ population distant from memory cells. By imaging mass cytometry, we find that MZ B cells and memory B cells occupy different microanatomical niches in organised gut lymphoid tissues. Both populations disseminate widely between distant lymphoid tissues and blood, and both diversify their IGHV repertoire in gut germinal centres (GC), but nevertheless remain largely clonally separate. MZ B cells are therefore not developmentally contiguous with or analogous to classical memory B cells despite their shared ability to transit through GC, where somatic mutations are acquired.

Key Points• hi , CD127 lo Tregs), expresses the interleukin-2 (IL-2)/STAT5 pathway and cell-cycle commitment genes. Furthermore, in vitro-expanded Tregs become functional and take on the characteristics of Treg B. Collectively, this study identifies human Treg subpopulations that can be used as predictive biomarkers for response to IST in AA and potentially other autoimmune diseases. We also show that Tregs from AA patients are IL-2-sensitive and expandable in vitro, suggesting novel therapeutic approaches such as low-dose IL-2 therapy and/or expanded autologous Tregs and meriting further exploration. (Blood. 2016;128(9):1193-1205