TABLE 2.

T1D candidate genes expressed in mononuclear phagocytes with their functional roles that may potentially alter tolerance

Candidate genes		Locationb		Known functions	Known roles in mononuclear phagocytes	References
Gene symbola	Gene name	Human T1D	Mouse NOD
AFF3	AF4/FMR2 family, member 3	2q11.2	chr1	May function as nuclear transcriptional activator in lymphoid and brain development	Is expressed in pDCs	[45]
			Idd26
BACH2	BTB and CNC homology 1, basic leucine zipper transcription factor 2	6q15	chr4	Is a transcriptional regulator that mediates B cell lineage development and represses CD4+ T cell differentiation	Regulates M1–M2 polarization; Bach2-deficient alveolar macrophages show enhanced cholesterol uptake and recruitment into lung	[46]
BAD	BCL2-associated agonist of cell death	11q13.1	chr19	Mediates proapoptotic signaling by forming heterodimers with BCL-xL and BCL-2	Mediates LPS/CpG-induced apoptosis in BM-DCs	[47]
C1QTNF6	C1q and TNF-related protein 6, CTRP6	22q12.3	chr15	Is an adiponectin paralog that can modulate metabolism, inflammation, and angiogenesis	Treatment of CTRP6 induces IL-10 production in human macrophage cell lines	[48]
CD226	CD226 molecule, DNAM-1	18q22.2	chr18	Stimulates NK cell-mediated cytotoxicity; expressed mainly on NK cells, platelets, T cells, and monocytes	Cross-linking CD226 mediates maturation of CD8α+ DCs	[49]
			Idd21.1
CD69	CD69 molecule	12p13.31	chr6	Regulates lymphocyte proliferation	Inhibits sphingosine-1-phosphate-induced skin DC migration; is expressed by pDCs	[50, 51]
CLEC16A	C-type lectin domain family 16, member A	16p13.13	chr16	Predominately expressed in DCs, B cells, and NK cells; is involved in the costimulation and activation of T cells	Promotes late endosomal maturation to drive MHC class II expression in human monocyte DCs	[52]
CTSH	Cathepsin H	15q25.1	chr9	Increases insulin and protects against cytokine-induced apoptosis in islet β cells	Is required for MHC-II antigen presentation in APCs; higher expression in hCD1c+ cDCs compared with hCD141+ cDCs	[53–55]
			Idd2
DEXI	Dexi homolog (mouse)	16p13.13	chr16	Unknown function; induced by dexamethasone; risk allele corresponds with lower DEXI mRNA expression	Is highly expressed on DCs and monocytes	[56]
DLK1	δ-like 1 homolog (Drosophila), δ-1	14q32.2	chr12c	Mediates normal adipogenesis, muscular and neuronal differentiation, bone differentiation, and hematopoiesis	Promotes human mDC differentiation; promotes Th1 differentiation through interaction with Notch1 on T cells	[57]
IL2RA	IL-2 receptor, α	10p15.1	chr2	Induces cell proliferation, differentiation, and survival/apoptosis	Blocking reduces LPS-stimulated inflammatory cytokines and Th1 priming by DCs; IL2RA+IDO+ DCs suppress T cell proliferation	[58]
		IDDM21
IL7R	IL-7 receptor	5p13.2	chr15	IL-7 is a growth factor for lymphoid progenitors; induces homeostatic T cell proliferation	Is required for cDC and pDC development from CLPs; down-regulates MHC expression on DCs	[59, 60]
NRP1	Neuropilin 1, BDCA-4	10p11.22	chr8	Is expressed in human pDCs, moDCs, and Tregs; is the receptor for Sema3A, VEGF and LAP-TGF-β1	Increases contact between resting T cells/Tregs and DCs; is transferred from DCs to T cells by trogocytosis	[61, 62]
ORMDL3	ORMDL sphingolipid biosynthesis regulator 3	17q12	chr11	Is involved in ER stress and inflammation; regulates eosinophil recruitment and degranulation in allergic asthma	Is induced on lung macrophages during allergic inflammation and increases chemokine expression	[63]
PTPN2	Protein tyrosine phosphatase, nonreceptor type 2	18p11.21	chr18	Is a negative regulator of tyrosine kinases that signal downstream of cytokine and antigen receptors; inactivates JAK/STAT signal	Suppresses CSF-1–mediated mononuclear phagocyte development	[64, 65]
			Idd21.2
PTPN22	Protein tyrosine phosphatase, nonreceptor type 22	1p13.2	chr3	Negatively regulates TCR signal in T cells; risk allele gives increase in memory/effector T cells	PTPN22 loss of function results in DC hyporesponsiveness	[66, 67]
			Idd18.2
RAC2	Ras-related C3 botulinum toxin substrate 2 (Rho family, small GTP binding protein Rac2)	22q12.3	chr15	Is a plasma membrane protein that regulates cell secretion, phagocytosis, and polarization	Rac2 deficiency in DCs impaired migration toward T cells and T cell priming; required for phagosomal pH regulation and cross-presentation in CD8+ DCs	[68, 69]
RASGRP1	RAS guanyl releasing protein 1 (calcium and DAG-regulated)	15q14	chr2	Regulates Ras activation in lymphocytes, a central determinant of Ag receptor signal strength	Is up-regulated by TLR agonists in macrophages and limits TLR-mediated inflammation	[70]
			Idd13
TAGAP	T cell activation Rho GTPase activating protein	6q25.3	chr17	Is a negative regulator that mediates Rho GTPase signaling in activated T cells and other immune cells	Tagap deficiency in macrophages reduces inflammatory responses, including IFN-β, and increased virus replication	[71]
		IDDM21	Idd23
TNFAIP3	TNF-α–induced protein 3, A20	6q23.3	chr10c	Tnfaip3 deficient DCs are spontaneously activated and produce high levels of proinflammatory cytokines	Tnfaip3 deficiency in DCs causes systemic autoimmunity in mice	[72, 73]
TYK2	Tyrosine kinase 2	19p13.2	chr9	Acts as JAK kinase for STAT signal for IFN-α, IL-12/IL-23, IL-10, GM-CSF stimulation	Tyk2 deficiency in DCs impaired Th1 differentiation	[94]

BM-DCs, bone marrow-derived DCs; moDCs, monocyte-derived DCs.

^aGenes not in bold (BACH2 and C1QTNF6) show DC gene expression by ImmGen database, but no other publications confirm DC expression.

^bWhere applicable, the relevant human IDDM or mouse Idd locus is given.

^cMouse DlK1 and TNFAIP3 have not been shown to affect NOD diabetes susceptibility.