Table 1.
Summary of APC functions affected in T1D
| APC functions and pathways | T1D (human) | T1D (rodents) | ||
|---|---|---|---|---|
| APC development (Supplementary Tables 4–6) | Cell number and yield | Fewer blood DCs (young subjects); reduced moDC yield in vitro | Fewer splenic DCs in vivo; reduced BM-DC yield in vitro | |
| APC generation and expansion | IKZF1* DC subsets?; SH2B3* DC numbers? GAB3*/ZFP36L1* monocyte and MΦ generation? GAB3*/PTPN2* response to M-CSF | Csf1M/Csf2M; responsiveness to M-CSF ↓ in MΦs Ptpn2M? | ||
| Antigen presentation | Antigen expression (Supplementary Table 7) | β-Cell autoantigens | INS*; IA-2/IGRP (splicing) | IappM; InsR |
| PTA regulation | DEAF1 (splicing) | Deaf1 (splicing) | ||
| MHC (Supplementary Tables 8–10) | MHC-II haplotype | HLA-DR3/4; DQ8/2 | I-Ag7 (M); RT1u (R) | |
| MHC-II expression | HLA-DR ↑ | MHC-II ↓ | ||
| SLC11A1* | Slc11a1M (↑ Nramp) | |||
| MHC-I | HLA-B; HLA-A | β2-microglobulinM/R | ||
| Antigen capture | Phagocytosis | FCGR2A* | Fcgr2M in MΦs; impaired clearance of apoptotic cells | |
| Antigen processing and loading (Supplementary Table 8) | Autophagy | CLEC16A*; CTSB* | ||
| Proteolysis | CTSB*; CTSH*; ERAP1*; PRSS16* | CtshM? | ||
| Peptide binding | CLIP; neoantigens (DRiP, HIP) | CLIP, HIP | ||
| Cross-presentation | RAC2*?; MAP3K14*? | Impaired in CD8α+ DCs; RAC2R? | ||
| APC activation and function | Maturation (Supplementary Table 11) | NF-κB pathway hyperactivity (monocytes, moDCs); MAP3K14* TNFAIP3* A20 ↓ | NF-κB pathway dysregulation and hyperactivity; Nfkb1R | |
| Costimulation (Supplementary Tables 9 and 10) | No consensus on costimulatory molecule expression; CD226* | No consensus on costimulatory molecule expression | ||
| Cytokines (Supplementary Tables 12 and 13) | IL10*; C1QTNF6*?; SLC11A1*? IL-10↓ in B cells | Il10M?; CD101M? C1qtnf6R? Slc11a1M? | ||
| IL27* | Il27R | |||
| IL-12 ↓ or ≡ in DCs; TYK2*?; STAT4*? SLC11A1*? | IL-12 ↓ in DCs; ↑ in MΦs; no consensus in BM-DCs; Slc11a1M? | |||
| IL-1β ↑ or ≡ in monocytes | Il1a/Il1bM/R | |||
| IFN-α/IFN-β ↑; IFIH1* TLR8*; TAGAP*; PTPN22* | IFN-α/IFN-β ↑ TagapM?; Ptpn22M | |||
| GM-CSF ↑ (monocytes) | GM-CSF ↑ (MΦs) | |||
| Tolerogenic function (Supplementary Table 14) | Defective Treg induction by lamina propria DCs; NRP1*?; B7-H4 ↓; galectin-1 ↓; CYP27B1* | Defective tolerance induction by CD8α+ DCs; B7-H4 ↓; IDO ↓ in DCs and fibroblasts | ||
| APC adhesion and homing (Supplementary Table 15) | Cell adhesion | ITGB1*; ITGB7*; ICAM-1 ↓ (monocytes) | Fibronectin adhesion ↑; SLAM ↓ | |
| Chemotaxis | CCR2 ↓; CCR5*; CCR7*; CXCL12*; GPR183*; SKAP2*; CD69* | CCR2 ↓; CCR5 ↓; CCR7M? CXCL12 ↑; Skap2R | ||
Genes associated with the disease are denoted by * for humans, M for NOD mice, or R for diabetes-prone BB rats; they are described in more details in Supplementary Tables 1, 2 (humans), and 3 (rodents). For more details about the genes or functions in each category, refer to the indicated supplementary tables. All functions listed under rodents are for NOD mice. Commonalities between patients and rodent models are in boldface type. A question mark indicates that the role of the gene in a particular function is speculative or that the gene association is not refined. When the same gene is linked to T1D in both humans and animal models, it is nonetheless possible that the function of that gene is affected differently between the two species. ↑, increased; ↓, decreased; ≡, unchanged. DRiP, defective ribosomal product; HIP, hybrid insulin peptide.