Altered Function of Antigen-Presenting Cells in Type 1 Diabetes: a Challenge for Antigen-Specific Immunotherapy?
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Diabetes Volume 67, August 2018 1481 Altered Function of Antigen-Presenting Cells in Type 1 Diabetes: A Challenge for Antigen-Specific Immunotherapy? Rémi J. Creusot, Jorge Postigo-Fernandez, and Nato Teteloshvili Diabetes 2018;67:1481–1494 | https://doi.org/10.2337/db17-1564 Type 1 diabetes (T1D) arises from a failure to maintain substantially overlap with other polygenic autoimmune tolerance to specific b-cell antigens. Antigen-specific and autoinflammatory diseases (Supplementary Table 1), immunotherapy (ASIT) aims to reestablish immune toler- and T1D patients may develop other autoimmune dis- ance through the supply of pertinent antigens to specific eases such as thyroiditis and celiac disease (2). Therefore, cell types or environments that are suitable for eliciting although a number of genetic traits may predispose to tolerogenic responses. However, antigen-presenting multiple autoimmune diseases, specificprecipitating METHODOLOGY REVIEW cells (APCs) in T1D patients and in animal models of T1D events may serve as a trigger and dictate which tissue(s) are affected by a number of alterations, some due to becomes targeted by autoreactive T cells. Whether it is genetic polymorphism. Combination of these alterations, deletion, anergy, or induction of regulatory T cells (Tregs), impacting the number, phenotype, and function of APC all mechanisms of tolerance require presentation of self- subsets, may account for both the underlying toler- antigens to thymocytes or peripheral T cells by tolero- ance deficiency and for the limited efficacy of ASITs genic antigen-presenting cells (APCs), which are equipped so far. In this comprehensive review, we examine dif- ferent aspects of APC function that are pertinent to to deliver, upon engagement of T cells, appropriate tolerance induction and summarize how they are al- signals to prevent or shut down unwanted responses. tered in the context of T1D. We attempt to reconcile The most studied are professional (hematopoietic) APCs, 25 years of studies on this topic, highlighting genetic, such as dendritic cells (DCs), macrophages (MFs), and phenotypic, and functional features that are common B cells. However, these APCs constitute double-edged or distinct between humans and animal models. Finally, swords in T1D because they may be inappropriately we discuss the implications of these defects and swayed toward immunogenic functions. Here, we com- the challenges they might pose for the use of ASITs to prehensively review APC features and functions that are treat T1D. Better understanding of these APC alterations relevant to tolerance (Fig. 1) and how they are altered or will help us design more efficient ways to induce toler- defective in humans and animals with T1D, including ance. genetic associations that may influence these functions (Table 1 and Supplementary Tables 2 and 3). We then discuss the implications of such APC alterations on the Type 1 diabetes (T1D) results from T-cell–mediated de- efficacy of antigen-specific immunotherapies (ASITs), struction of insulin-producing pancreatic b-cells, leading which aim to deliver particular self-antigens to the to hyperglycemia and associated complications (1). The patient’s endogenous populations of APCs for toler- etiology of T1D is not completely understood, but both ance induction (Fig. 2 and Table 2). In the context of genetic and environmental factors are known contrib- this review, we define APC as any cell that can pre- utors in conjunction with a decline of central and pe- sent self-antigens and may potentially be the target of ripheral tolerance mechanisms. T1D susceptibility genes ASITs. Columbia Center for Translational Immunology, Naomi Berrie Diabetes Center and © 2018 by the American Diabetes Association. Readers may use this article as Department of Medicine, Columbia University Medical Center, New York, NY long as the work is properly cited, the use is educational and not for profit, and the Corresponding author: Rémi J. Creusot, [email protected]. work is not altered. More information is available at http://www.diabetesjournals .org/content/license. Received 22 December 2017 and accepted 3 May 2018. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db17-1564/-/DC1. 1482 Altered APCs in T1D and Immunotherapy Diabetes Volume 67, August 2018 Figure 1—Summary of APC biological processes affected in T1D with examples. Processes shown are from multiple APCs (DCs, MFs, B cells, mTECs, stromal cells) and may not all be found in a given type of APC. (1) and (-) denote immunogenic and tolerogenic signals, respectively. Ag, antigen; DRiP, defective ribosomal product; FcR, Fc receptors; HIP, hybrid insulin peptide; VDR, vitamin D receptor. APC DEVELOPMENT AND FREQUENCIES levels of FLT3L or other growth factors are responsible for The relative proportion of different types of APCs may the reduced number of certain DC subsets. Candidate influence the frequency of their interactions with self- genes for other pertinent growth factors in NOD suscepti- reactive T cells and the subsequent phenotype of these bility regions include Csf1 (Idd18.3, encoding macrophage T cells. Peripheral blood DCs are differentially altered in colony-stimulating factor [M-CSF]) and Csf2 (Idd4.3, encod- their proportions depending on the age and disease stage ing granulocyte-macrophage colony-stimulating factor [GM- (new-onset or long-term T1D vs. control group) of subjects CSF]) (Supplementary Table 3). Polymorphism on these (Supplementary Table 4A). The youngest patients appear genes (and perhaps others) or altered responsiveness to to have a deficit in both myeloid DCs (mDCs) and plas- these cytokines may affect the development and differ- macytoid DCs (pDCs), although this difference is not entiation of myeloid APC progenitors or the function of apparent when evaluating a broader age range. The term myeloid cells (Supplementary Table 6). On the one hand, mDC is now obsolete, but in most studies listed (Supple- MFs from NOD mice and monocytes from T1D patients 1 2 mentary Table 4), it refers to CD11c CD123 DCs, and in and high-risk subjects express higher basal levels of GM-CSF, 1 a few studies, specifically to migratory CD1c DCs. Further- leading to persistent STAT5 stimulation. This increased more, fewer monocyte-derived DCs (moDCs) were obtained GM-CSF production is somewhat surprising given the gen- from T1D or at-risk patients compared with control subjects erally reported lower frequency of DCs and the therapeutic (Supplementary Table 4B). Polymorphism in several human benefit of GM-CSF in T1D (3). On the other hand, re- susceptibility genes may impact the development and number sponsiveness to M-CSF is reduced in NOD mice (Supple- of APCs, including SH2B3 for DCs, IKZF1 for mDCs and mentary Table 6) and may be influenced in humans by the pDCs, and GAB3 and ZFP36L1 for monocytes and MFs susceptibility genes GAB3 and PTPN2,whichencodesig- (Supplementary Table 2). naling components downstream of the M-CSF receptor Studies in NOD mice have made it possible to analyze (Supplementary Table 2). APC frequency, phenotype, and function beyond the pe- MerocyticDCs,alesser-knownpopulationof 1 2 2 ripheral blood. NOD mice have consistently yielded fewer CD11c CD8a CD11b /low DCs that can break the toler- 1 splenic DCs, particularly splenic CD8a DCs (Supplemen- ance to apoptotic cell–derived antigens, are increased in tary Table 5A). Similarly, the yield of bone marrow-derived NOD mice compared with other strains (4). Pancreatic DCs (BM-DCs) generated in vitro was reduced in NOD mice islets contain several populations of DCs and MFs(5–7). 1 1 in the great majority of studies (Supplementary Table 5B). The majority of islet DCs are CD11b CX3CR1 DCs that Defects affecting in vivo DC subsets, as well as pDC pre- are potentially proinflammatory and increase over time, 1 cursors, could be corrected by treatment with FLT3L (Sup- whereas CD103 DCs represent a minority that typi- plementary Table 6). However, it is unclear if insufficient cally migrate to pancreatic lymph nodes (PLNs) to present Table 1—Summary of APC functions affected in T1D APC functions and pathways T1D (human) T1D (rodents) 1483 APC development (Supplementary Tables 4–6) Cell number and yield Fewer blood DCs (young subjects); Fewer splenic DCs in vivo; reduced moDC yield in vitro reduced BM-DC yield in vitro APC generation and IKZF1* DC subsets?; SH2B3* DC numbers? Csf1M/Csf2M; responsiveness expansion GAB3*/ZFP36L1* monocyte and MF generation? to M-CSF ↓ in MFs GAB3*/PTPN2* response to M-CSF Ptpn2M? Antigen Antigen expression b-Cell autoantigens INS*; IA-2/IGRP (splicing) IappM; InsR presentation (Supplementary Table 7) PTA regulation DEAF1 (splicing) Deaf1 (splicing) u MHC (Supplementary Tables MHC-II haplotype HLA-DR3/4; DQ8/2 I-Ag7 (M); RT1 (R) 8–10) MHC-II expression HLA-DR ↑ MHC-II ↓ SLC11A1* Slc11a1M (↑ Nramp) MHC-I HLA-B; HLA-A b2-microglobulinM/R Antigen capture Phagocytosis FCGR2A* Fcgr2M in MFs; impaired clearance of apoptotic cells Antigen processing and loading Autophagy CLEC16A*; CTSB* (Supplementary Table 8) Proteolysis CTSB*; CTSH*; ERAP1*; PRSS16* CtshM? Peptide binding CLIP; neoantigens (DRiP, HIP) CLIP, HIP 1 Cross-presentation RAC2*?; MAP3K14*? Impaired in CD8a DCs; RAC2R? APC activation and function Maturation (Supplementary NF-kB pathway hyperactivity NF-kB pathway dysregulation and Table 11) (monocytes, moDCs); MAP3K14* TNFAIP3* A20 ↓ hyperactivity; Nfkb1R Costimulation No consensus on costimulatory No consensus on costimulatory (Supplementary