Identification of a Structurally Distinct CD101 Molecule Encoded in the 950-kb<i>Idd10</i>Region of NOD Mice

Penha‐Gonçalves, Carlos; Moule, Carolyn; Smink, Luc J.; Howson, Joanna M.M.; Gregory, Simon G.; Rogers, Jane; Lyons, Paul; Suttie, Joseph; Lord, Christopher J.; Peterson, Laurence B.; Todd, John A.; Wicker, Linda S.

doi:10.2337/diabetes.52.6.1551

Cited by 29 publications

(38 citation statements)

References 26 publications

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“…However, two recent studies of gene clusters associated with autoimmune type 1 diabetes susceptibility in the NOD mouse (Idd loci) identified CD101 as a candidate gene involved in the development of diabetes (35,36). Genetic polymorphisms that lead to an altered amino acid structure of the CD101 protein could ultimately lead to numeric (37) or functional deficits of the Treg pool as has been reported for autoimmune type 1 diabetes.…”

Section: Discussionmentioning

confidence: 95%

CD101 Surface Expression Discriminates Potency Among Murine FoxP3+ Regulatory T Cells

Fernández¹,

Zeiser

Karsunky³

et al. 2007

The Journal of Immunology

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CD4+CD25+FoxP3+ regulatory T cells (Treg) have been shown to be protective in animal models of autoimmunity and acute graft-vs-host disease. However, owing to the functional heterogeneity among CD4+CD25+ T cells, surface markers expressed selectively on functionally active Treg would be useful for purposes of identifying and isolating such cells. We generated a rabbit mAb against murine CD101, a transmembrane glycoprotein involved in T cell activation. Among freshly isolated T cells, CD101 was detected on 25-30% of CD4+CD25+ Treg and approximately 20% of conventional memory T cells. CD101(high) Treg displayed greater in vitro suppression of alloantigen-driven T cell proliferation as compared with CD101(low) Treg. In a model of graft-vs-host disease induced by allogeneic bone marrow transplantation in vivo bioluminescence imaging demonstrated reduced expansion of donor-derived luciferase-labeled conventional T cells in mice treated with CD101(high) Treg, compared with CD101(low) Treg. Moreover, treatment with CD101(high) Treg resulted in improved survival, reduced proinflammatory cytokine levels and reduced end organ damage. Among the CD101(high) Treg all of the in vivo suppressor activity was contained within the CD62L(high) subpopulation. We conclude that CD101 expression distinguishes murine Treg with potent suppressor activity.

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Section: Discussionmentioning

confidence: 95%

CD101 Surface Expression Discriminates Potency Among Murine FoxP3+ Regulatory T Cells

Fernández¹,

Zeiser

Karsunky³

et al. 2007

The Journal of Immunology

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“…Genetic susceptibility of T1D has been extensively studied, and a number of candidate genes, including MHC and non-MHC genes, have been identified (7,(31)(32)(33)(34)(35). Although the identity of the susceptibility genes that are specifically active in T cells is not clear, the expression of susceptibility genes in T cells may help autoreactive T cells escape from negative selection or enhance responses in the periphery (36,37).…”

Section: Discussionmentioning

confidence: 99%

Diabetes Resistance/Susceptibility in T Cells of Nonobese Diabetic Mice Conferred by MHC and MHC-Linked Genes

Ueno

Cho

et al. 2005

The Journal of Immunology

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Polymorphism of MHC and MHC-linked genes is tightly associated with susceptibility to type 1 diabetes (T1D) in human and animal models. Despite the extensive studies, however, the role of MHC and MHC-linked genes expressed by T cells on T1D susceptibility remains unclear. Because T cells develop from TCR− thymic precursor (pre-T) cells that undergo MHC restriction mediated by thymic stroma cells, we reconstituted the T cell compartment of NOD.scid-RIP-B7.1 mice using pre-T cells isolated from NOD, NOR, AKR, and C57BL/6 (B6) mice. T1D developed rapidly in the mice reconstituted with pre-T cells derived from NOD or NOR donors. In contrast, most of the NOD.scid-RIP-B7.1 mice reconstituted with pre-T cells from AKR or B6 donors were free of T1D. Further analysis revealed that genes within MHC locus of AKR or B6 origin reduced incidence of T1D in the reconstituted NOD.scid-RIP-B7.1 mice. The expression of MHC class I genes of k, but not b haplotype, in T cells conferred T1D resistance. Replacement of an interval near the distal end of the D region in T cells of B6 origin with an identical allele of 129.S6 origin resulted in T1D development in the reconstituted mice. These results provide evidence that the expression of MHC class I and MHC-linked genes in T cells of NOD mice indeed contributes to T1D susceptibility, while expression of specific resistance alleles of MHC or MHC-linked genes in T cells alone would effectively reduce or even prevent T1D.

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“…21 Tspan-2, which is one of the candidates for Cia21, 5 is also a possible candidate for the insulin-dependent diabetes loci 10, Idd10, mapped to the same region. 22 The gene was upregulated in spleen in the Cia5 congenic compared to the parental strain 12 days after immunization. Tspan-2 encodes a protein participating in the membrane dynamics required for proper T-cell signaling.…”

Section: Discussionmentioning

confidence: 96%

“…14 The selection of genes was unbiased.The function of the genes was not taken into account. However, a few genes located in the Cia5 fragment but not within the selected QTL region were added to the list because they had previously been reported as possible candidates 22 or because they were differently expressed in the genome wide profiling experiment. The complete gene list is presented in Supplementary Table 1.…”

Section: Design Of the Qtl Chipmentioning

confidence: 99%

Gene expression profiling of arthritis using a QTL chip reveals a complex gene regulation of the Cia5 region in mice

et al. 2005

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One of the major quantitative trait loci (QTLs) associated with arthritis in crosses between B10.RIII and RIIIS/J mice is the Cia5 on chromosome 3. Early in the congenic mapping process it was clear that the locus was complex, consisting of several subloci with small effects. Therefore, we developed two novel strategies to dissect a QTL: the partial advanced intercross (PAI) strategy, with which we recently found the Cia5 region to consist of three loci, Cia5, Cia21 and Cia22, and now we introduce the QTL-chip strategy, where we have combined congenic mapping with a QTL-restricted expression profiling using a novel microarray design. The expression of QTL genes was compared between parental and congenic mice in lymph node, spleen and paw samples in five biological replicates and in dye-swapped experiments at three time points during the induction phase of arthritis. The QTL chip approach revealed 4 genes located in Cia21, differently expressed in lymph nodes, and 14 genes in Cia22, located within two clusters. One cluster contains six genes, differently expressed in spleen, and the second cluster contains eight genes, differently expressed in paws. We conclude the QTL-chip strategy to be valuable in the selection of candidate genes to be prioritized for further investigation.

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Identification of a Structurally Distinct CD101 Molecule Encoded in the 950-kbIdd10Region of NOD Mice

Cited by 29 publications

References 26 publications

CD101 Surface Expression Discriminates Potency Among Murine FoxP3+ Regulatory T Cells

CD101 Surface Expression Discriminates Potency Among Murine FoxP3+ Regulatory T Cells

Diabetes Resistance/Susceptibility in T Cells of Nonobese Diabetic Mice Conferred by MHC and MHC-Linked Genes

Gene expression profiling of arthritis using a QTL chip reveals a complex gene regulation of the Cia5 region in mice

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