The number of β cells, determined from β cell mass [17–20], is an outcome of developmental turnover and the level of autoimmune destruction [13,16,19,21]. β cell insulin production is regulated by the levels of glucose and inflammatory mediators [22,23]. Autoantigens.  Autoantigens are modelled generically to represent several antigens identified in the literature, including insulin and glutamic acid decarboxylase [24,25]. The autoantigen level is a function of β cell mass, β cell apoptosis and insulin secretion. Autoantigens are acquired and presented on major histocompatibility complex (MHC) class I and II molecules by dendritic cells (DCs), macrophages and B lymphocytes [26–28].

β cells also present autoantigens on MHC class I molecules [29]. Dendritic cells.  DCs are present in each modelled islet, even in the absence of inflammation, and recruitment of DC precursors is amplified by inflammation [30,31]. Both Sunitinib mouse inflammatory and suppressive (tolerogenic) DC phenotypes are represented [32,33]. Each subset influences the developing adaptive immune response, and each has limited phagocytic capabilities [34]. DCs acquire

and present antigens, produce mediators, interact with other cell types and traffic from the islets to the PLN Palbociclib order [26,35–37]. Macrophages.  Macrophages are also present in the islets even in the absence of inflammation, and recruitment of macrophage precursors is amplified by inflammation [38,39]. Macrophages perform phagocytic functions, acquire and present antigens, produce mediators, interact with other cell types and traffic to the PLN [27,37,40,41]. CD4+ T lymphocytes.  Two groups of naive CD4+ T lymphocytes are represented: those specific for islet autoantigens and those specific for other antigens. This same distinction is made for all other T lymphocyte and B lymphocyte populations. In the model, thymic output of naive T MRIP cells is a specified time-dependent

profile representative of what has been observed experimentally [42–44], taking into account the relative proportion of CD4+ and CD8+ T cells [45], but is not regulated dynamically. While the intricate and highly regulated process of thymocyte development has been studied extensively, it was not included in the current model scope based on an initial focus on peripheral mechanisms of autoimmunity and tolerance. The validation protocols used to refine and test virtual mouse behaviours were dependent primarily on peripheral mechanisms. However, the model was designed to accommodate expansion of the represented biology, which could include thymocyte development. During simulations, naive islet-autoantigen-specific (or diabetes-specific) T lymphocytes in the PLN become activated in response to autoantigen presented on MHC class II molecules and differentiate into T helper type 1 (Th1), Th2 or regulatory T cell (adaptive regulatory T cell or aTreg) subsets [46–49].