Genetic and functional data identifying Cd101 as a type 1 diabetes (T1D) susceptibility gene in nonobese diabetic (NOD) mice

Abstract

Type 1 diabetes (T1D) is a chronic multi-factorial disorder characterized by the immune-mediated destruction of insulin-producing pancreatic beta cells. Variations at a large number of genes influence susceptibility to spontaneous autoimmune T1D in non-obese diabetic (NOD) mice, one of the most frequently studied animal models for human disease. The genetic analysis of these mice allowed the identification of many insulin-dependent diabetes ( Idd ) loci and candidate genes, one of them being Cd101 . CD101 is a heavily glycosylated transmembrane molecule which exhibits negative-costimulatory functions and promotes regulatory T (Treg) function. It is abundantly expressed on subsets of lymphoid and myeloid cells, particularly within the gastrointestinal tract. We have recently reported that the genotype-dependent expression of CD101 correlates with a decreased susceptibility to T1D in NOD.B6 Idd10 congenic mice compared to parental NOD controls. Here we show that the knockout of CD101 within the introgressed B6-derived Idd10 region increased T1D frequency to that of the NOD strain. This loss of protection from T1D was paralleled by decreased Gr1-expressing myeloid cells and FoxP3 + Tregs and an enhanced accumulation of CD4-positive over CD8-positive T lymphocytes in pancreatic tissues. As compared to CD101 +/+ NOD.B6 Idd10 donors, adoptive T cell transfers from CD101 −/− NOD.B6 Idd10 mice increased T1D frequency in lymphopenic NOD scid and NOD.B6 Idd10 scid recipients. Increased T1D frequency correlated with a more rapid expansion of the transferred CD101 −/− T cells and a lower proportion of recipient Gr1-expressing myeloid cells in the pancreatic lymph nodes. Fewer of the Gr1 + cells in the recipients receiving CD101 −/− T cells expressed CD101 and the cells had lower levels of IL-10 and TGF-β mRNA. Thus, our results connect the Cd101 haplotype-dependent protection from T1D to an anti-diabetogenic function of CD101-expressing Tregs and Gr1-positive myeloid cells and confirm the identity of Cd101 as Idd10 .

Galectin-1 correlates with inflammatory markers and T regulatory cells in children with type 1 diabetes and/or celiac disease

“…However, in children with T1D, GAL-1 correlated positively with CD25 MFI in Treg cells, as well as with both the number and frequency of CD101 + Treg cells. CD101 has previously been identified as a T1D susceptibility gene and is proposed to restrain the expansion of diabetogenic CD4 and CD8 expressing T lymphocytes and reduce T1D frequency in NOD mice [ 56 ]. It is thus possible that interaction between GAL-1 and CD101 is a shared pathway in the development of T1D.…”

Identification of biomarkers and pathways for focal segmental glomerulosclerosis using next generation sequencing data and bioinformatics analysis

“…Pathways include metabolism [42], transport of small molecules [43] and immune system [44] are linked with progression of FSGS. PDK4 [45], ALB (albumin) [46], EGR1 [47], RYR3 [48], APOH (apolipoprotein H) [49], CYP27B1 [50], ESM1 [51], GATA6 [52], PCK1 [53], TET2 [54], AFP (alpha fetoprotein) [55], CACNA1D [56], ATF3 [57], EGF (epidermal growth factor) [58], LPL (lipoprotein lipase) [59], PPARGC1A [60], PLG (plasminogen) [61], NR4A1 [62], STRA6 [63], MLXIPL (MLX interacting protein like) [64], PLA2G6 [65], RGS2 [66], GPS2 [67], SOX5 [68], GLUL (glutamate-ammonia ligase) [69], RYK (receptor like tyrosine kinase) [70], NFKBIA (NFKB inhibitor alpha) [71], LGR4 [72], SPRY2 [73], TRPC1 [74], KL (klotho) [75], GCLC (glutamate-cysteine ligase catalytic subunit) [76], NOX4 [77], CD69 [78], SLC19A2 [79], S100A12 [80], MT1A [81], SORCS1 [82], FKBP5 [83], AFM (afamin) [84], CA3 [85], MAOA (monoamine oxidase A) [86], ND1 [87], ATP6 [88], CHGA (chromogranin A) [89], ICOS (inducible T cell costimulator) [90], DBH (dopamine beta-hydroxylase) [91], CD5 [92], LTA (lymphotoxin alpha) [93], IFNG (interferon gamma) [94], MPO (myeloperoxidase) [95], CD70 [96], CD300E [97], COLEC12 [98], TLR10 [99], LCN2 [100], SLAMF7 [101], TREM2 [102], ITGAL (integrin subunit alpha L) [103], CD27 [104], JAK3 [105], CCR5 [106], FCN1 [107], IL1RN [108], CX3CR1 [109], PDCD1 [110], TRPM2 [111], PLEK (pleckstrin) [112], CD101 [113],...…”

“…The GO [64], PLA2G6 [65], RGS2 [66], GPS2 [67], SOX5 [68], GLUL (glutamate-ammonia ligase) [69], RYK (receptor like tyrosine kinase) [70], NFKBIA (NFKB inhibitor alpha) [71], LGR4 [102], ITGAL (integrin subunit alpha L) [103], CD27 [104], JAK3 [105], CCR5 [106], FCN1 [107], IL1RN [108], CX3CR1 [109], PDCD1 [110], TRPM2 [111], PLEK (pleckstrin) [112], CD101 [113], TNF (tumor necrosis factor) [114], CD48 [115], ALOX5 [116], TLR7 [117], CCL3 [118], C2 [119], TNFRSF1B [120], CCR2 [121], PLA2G7 [122], TH (tyrosine hydroxylase) [123], WNT7A [124], ADRB3 [125], GPBAR1 [126], SLC6A20 [127], FUT2 [128], ANK1 [129], NOS3 [130], APLNR (apelin receptor) [131], COMP (cartilage oligomeric matrix protein) [132], RETN (resistin) [133], NMU (neuromedin U) [134], S100B [135], IGFBP1 [136], COL1A1 [137], HBB (hemoglobin subunit beta) [138] and PLAC8 [139] genes plays important regulatory roles in diabetes mellitus. Various genes such as PDK4 [140], ALB (albumin) [141], EGR1 [142], RYR3 [48], CYP27B1 [143], GATA6 [144], NR4A3 [145], TET2…”

Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes

“…Similarly, the frequency of T follicular regulatory (Tfr) cells, a specialized regulatory counterpart of T follicular helper (Tfh) cells, is reduced in PLNs of T1D patients, and re-supplementation of Tfr cells delays T1D development in mice [ 92 ]. The unbalanced immune status of human T1D is featured by functional defects in CD4 + CD25 + Tregs in PLNs but not in peripheral blood [ 93 , 94 ]. PLN Tregs inhibit in situ differentiation of islet-reactive CD8 + T cells, and the suppression is mediated by the TGF-β/TGF-βRII axis, as Treg cells could not control naïve or activated islet-reactive CD8 + T cells bearing a dominant-negative TGF-βRII genotype following adoptive transfer [ 95 ].…”