Volume 32, Issue 4, Pages 437-445 (April 2010) The Long and Winding Road to Understanding and Conquering Type 1 Diabetes  Pere Santamaria  Immunity  Volume 32, Issue 4, Pages 437-445 (April 2010) DOI: 10.1016/j.immuni.2010.04.003 Copyright © 2010 Elsevier Inc. Terms and Conditions

Figure 1 Intersection of T1D Pathways and T1D-Associated Genes High-avidity (HA) autoreactive CD4+ and CD8+ T cells escape thymic negative selection and populate the peripheral lymphoid organs. Unknown insults trigger β cell autoantigen shedding into the milieu. Antigen-presenting cells (APCs; e.g., DCs and/or B cells) then ferry these autoantigens to the pancreatic LNs, where they prime naïve HA autoreactive CD4+ and CD8+ T cells. CD8+ T cells become activated upon engaging cognate pMHC class I on autoantigen-loaded APCs in the presence of HA autoreactive CD4+ T helper cells, proinflammatory mediators (IL-2 and other cytokines), and/or endogenous or exogenous “danger signals.” These HA autoreactive CD8+ and CD4+ T cells expand, differentiate into CTLs, and migrate via the bloodstream into pancreatic islets, where they effect β cell damage through various means. FoxP3+CD4+CD25+ Treg cells are recruited to the PLN (and islets) in response to antigen and/or IL-2 and attempt to suppress autoantigen presentation and T cell activation. Upon chronic stimulation with cognate pMHC, low-avidity (LA) autoreactive CD8+ T cells differentiate into memory-like autoregulatory CD8+ T cells and suppress the presentation of autoantigens via a number of mechanisms, including APC cytotoxicity. Current evidence suggests that different T1D-associated genes encode molecules (labeled in red) that target some of these pathways. Immunity 2010 32, 437-445DOI: (10.1016/j.immuni.2010.04.003) Copyright © 2010 Elsevier Inc. Terms and Conditions