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4). of inducing antigen-specific tolerance when confronted with ongoing autoimmunity and have also recognized Zbtb32 as a suppressive transcription factor that controls T cellmediated autoimmunity. == Introduction == Antigen-specific induction of T-cell tolerance is a desired therapeutic Lofendazam end result for type 1 diabetes because of the potential to stop undesirable pathogenic responses while minimizing nonspecific immune inhibition. To date, little clinical efficacy has been observed for this approach (1,2). Autoimmune individuals elicit immune responses in an inflammatory context and are therefore refractory to tolerance induction, yet most studies of T-cell tolerance have been performed in either a steady-state context or in models of autoimmunity requiring immunization with autoantigen that best model the effector phase (3). Therefore, to move beyond therapies that nonspecifically block effector functions, it is important to learn what conditions are needed to enable antigen-specific T-cell tolerance induction in a chronic inflammatory autoimmune environment, which can be modeled using autoimmune-prone nonobese diabetic (NOD) mice that show spontaneous loss of self-tolerance due to genetic and environmental factors (4). These factors leading to autoimmune diabetes alter the capacity of antigen-presenting cell populations to induce tolerance (5). In NOD mice, dendritic cells (DCs) are in the pancreas prior to T-cell infiltration and are important for diabetes pathogenesis and regulation (68). DCs are central for both induction of immunity and tolerance (9), and standard DCs (cDCs) can be divided into two broad subsets with comparable function in both mouse and human (10). The cross-presenting cDC1 express XCR1 in both human and mouse and can be recognized by CD8 or CD103 expression in IMPG1 antibody mice (11,12). cDC2 are CD11b+in both mouse and human, CD1c+in human, and DC inhibitory receptor 2 (DCIR2)+in mice (10). CD11b+cDC2 are strong stimulators of antibody production and CD4+effector T-cell (Teff) responses and induce regulatory T-cell (Treg) proliferation, whereas CD8+cDC1 endocytose apoptotic blebs and can result in T-cell tolerance directed against self-antigens (13,14). cDC1 are dependent on the transcription factor Batf3, and loss of Batf3 in NOD mice leads to a block in diabetes pathogenesis (12,15). Patients with type 1 diabetes and NOD mice carry diabetes susceptibility alleles, some of which impact antigen-presenting cells, such as DCs, that lead to a loss of tolerance and development of autoimmune diabetes (16). The normal generation and maintenance of DCs may be altered in autoimmune diabetes and impact T-cell tolerance induction (1719). T cells appear in the pancreas of NOD Lofendazam mice as early as 4 weeks of age, but hyperglycemia does not occur until 12 weeks or later. This can be modeled by CD4+autoreactive BDC2.5 T-cell receptor (TCR) transgenic T cells that respond to the -cell granule protein chromogranin A as well as a series of mimetope peptides (2022). Prediabetic mice and humans show islet-specific T cells and antibody responses indicating active autoimmunity, but simultaneous immune regulation can slow -cell destruction (2325). Unlike some autoimmune diseases, the early phases of autoimmune diabetes are clinically silent because sufficient -cell destruction for hyperglycemia Lofendazam does not occur until late. Autoantibodies and MRI transmission present in prediabetic mice Lofendazam and humans correlate with immune infiltrate in the pancreatic islets (26,27), and individuals with high risk can now be identified prior to hyperglycemia (28). Therefore, this prediabetic phase represents ongoing autoimmunity Lofendazam and is of interest as a target of immunotherapy. Targeting antigen.