The Role of Dendritic Cell Maturation in the Induction of Insulin-Dependent Diabetes Mellitus

Abstract

Dendritic cells (DCs) are the dominant class of antigen-presenting cells in humans and are largely responsible for the initiation and guidance of innate and adaptive immune responses involved in maintenance of immunological homeostasis. Immature dendritic cells (iDCs) phagocytize pathogens and toxic proteins and in endosomal vesicles degrade them into small fragments for presentation on major histocompatibility complex (MHC) II receptor molecules to naïve cognate T cells (Th0). In addition to their role in stimulation of immunity, DCs are involved in the induction and maintenance of immune tolerance toward self-antigens. During activation, the iDCs become mature. Maturation begins when the DCs cease taking up antigens and begin to migrate from their location in peripheral tissues to adjacent lymph nodes or the spleen where during their continued maturation the DCs present stored antigens on surface MHCII receptor molecules to naive Th0 cells. During antigen presentation, the DCs upregulate the biosynthesis of costimulatory receptor molecules CD86, CD80, CD83, and CD40 on their plasma membrane. These activated DC receptor molecules bind cognate CD28 receptors presented on the Th0 cell membrane, which triggers DC secretion of IL-12 or IL-10 cytokines resulting in T cell differentiation into pro- or anti-inflammatory T cell subsets. Although basic concepts involved in the process of iDC activation and guidance of Th0 cell differentiation have been previously documented, they are poorly defined. In this review, we detail what is known about the process of DC maturation and its role in the induction of insulin-dependent diabetes mellitus autoimmunity.

A personalised approach for identifying disease-relevant pathways in heterogeneous diseases

“…These were the pathways involving MHC class protein and dendritic cell (DC) maturation. Even though these pathways are highly relevant in the context of the disease, they mostly represent only the initiating events in the development of the disease: release of autoantigens; their uptake by antigen presenting cells (APCs), such as DCs, for antigen presentation in a complex with MHC class proteins [Bending et al, 2012]; and migration of DCs to pancreatic lymph nodes (pLN) to activate β-cell specific autoreactive T cells [Bending et al, 2012;Clark et al, 2017], known as DC maturation [Mbongue et al, 2017]. Meanwhile, other important and disease-relevant pathways are underrepresented using the combined model.…”

“…One of the most interesting questions that are asked in T1D studies is regarding the changes that transpire in the time-window leading up to life-changing events, such as seroconversion and clinical onset of T1D. Using the personalised approach, multiple immunologically relevant pathways were revealed to be uniquely enriched in both the time-windows of interest, such as TNF signalling, where TNF-α has been linked to the development of T1D [Lee et al, 2005;Bending et al, 2012;Clark et al, 2017;Souto et al, 2014;Borish et al, 2003]; DC differentiation and maturation [Mbongue et al, 2017;Souto et al, 2014]; and cytokine-mediated signalling [Bending et al, 2012;Clark et al, 2017;Peakman, 2013], which acts like an all-encompassing, but vague, pathway for all cytokines. The method was able to determine additional relevant pathways in these two time-windows that were not identifiable by Kallionpää et al [2014] results: immunoglobulin production as well as IL-2 and IL-10 regulating pathways.…”

“…Especially, the number of cytokine regulating pathways were increased manifold, where more than half were unique to this time-window. Along with anti-inflammatory cytokines, such as IL-10 and IL-4 [Qiao et al, 2016;Borish et al, 2003;Souto et al, 2014], many pro-inflammatory cytokine regulating pathways were enriched, such as IL-1, IL-1β, IL-5 [Borish et al, 2003], IL-6 [Souto et al, 2014;Borish et al, 2003], IL-12 [Mbongue et al, 2017], IL-21 [Bending et al, 2012;Clark et al, 2017;Li et al, 2014], IL-22 [Borish et al, 2003], IFNγ, TNF-α. In the absence of IFNγ and TNF-α, cytokines IL-2, IL-1β and IL-6 are considered anti-inflammatory [Souto et al, 2014;Clark et al, 2017;Bending et al, 2012;Hartemann and Bourron, 2012;Pérol et al, 2016;Borish et al, 2003], but in their presence, these cytokines aggravate the inflammatory disease pattern, which is probably the case in the time time-window before T1D diagnosis.…”

“…IL-1 is a pro-inflammatory cytokine that enhances the production of IL-2, encourages B cell proliferation, and increases immunoglobulin production [Borish et al, 2003;Hartemann and Bourron, 2012]; whereas IL-4 is an anti-inflammatory Th2 cytokine that inhibits autoimmunity by down-regulating the production of pro-inflammatory cytokines, such as IL-1, IL-6 and TNF-α [Borish et al, 2003;Souto et al, 2014;Qiao et al, 2016]. Through mice studies, IFNα and PD-1 signalling pathways have been established as important contributors to T1D pathogenesis from an early stage of the disease [Marro et al, 2017;Li et al, 2008;Mbongue et al, 2017;Martinov et al, 2016]. Where up-regulation of IFNα in pLN is an initiator of the pathogenesis , up-regulation of programmed cell death protein 1 (PD-1) signalling prevents T1D and promotes self-tolerance by suppressing the expansion and infiltration of autoreactive T cells in the pancreas [Granados et al, 2017;Martinov et al, 2016;Mbongue et al, 2017].…”

“…Through mice studies, IFNα and PD-1 signalling pathways have been established as important contributors to T1D pathogenesis from an early stage of the disease [Marro et al, 2017;Li et al, 2008;Mbongue et al, 2017;Martinov et al, 2016]. Where up-regulation of IFNα in pLN is an initiator of the pathogenesis , up-regulation of programmed cell death protein 1 (PD-1) signalling prevents T1D and promotes self-tolerance by suppressing the expansion and infiltration of autoreactive T cells in the pancreas [Granados et al, 2017;Martinov et al, 2016;Mbongue et al, 2017]. In fact, blocking IFNα signalling before clinical T1D onset has been shown to prevent β-cell apoptosis or even abort T1D progression [Marro et al, 2017].…”