Person: Kissler, Stephan
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Kissler
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Stephan
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Kissler, Stephan
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Publication Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity(American Association for the Advancement of Science (AAAS), 2018-06-12) Duke-Cohan, Jonathan; Ishikawa, Yuki; Yoshizawa, Akihiro; Choi, Young-Il; Lee, Chin-Nien; Kissler, Stephan; Reinherz, Ellis L.Multiple autoimmune pathologies are associated with single-nucleotide polymorphisms of the human gene TAGAP, which encodes TAGAP, a guanosine triphosphatase (GTPase)-activating protein. We showed in mice that Tagap-mediated signaling by the sema3E/plexin-D1 ligand-receptor complex attenuates thymocytes' adhesion to the cortex through their beta1-containing integrins. By promoting thymocyte detachment within the cortex of the thymus, Tagap-mediated signaling enabled their translocation to the medulla, which is required for continued thymic selection. Tagap physically interacted with the cytoplasmic domain of plexin-D1 and directly stimulated the activity and signaling of the GTPase RhoA. In addition, Tagap indirectly mediated the activation of Cdc42 in response to the binding of sema3E to plexin-D1. Both RhoA and Cdc42 are key mediators of cytoskeletal and integrin dynamics in thymocytes. Knockdown of Tagap in mice suppressed the sema3E- and plexin-D1-mediated release of thymocytes that adhered within the cortex through beta1-containing integrins. This suppression led to the impaired translocation of thymocytes from the cortex to the medulla and resulted in the formation of ectopic medullary structures within the thymic cortex. Our results suggest that TAGAP variation modulates the risk of autoimmunity by altering thymocyte migration during thymic selection.Publication PTPN22 Silencing in the NOD Model Indicates the Type 1 Diabetes–Associated Allele Is Not a Loss-of-Function Variant(American Diabetes Association, 2013) Zheng, Peilin; Kissler, StephanPTPN22 encodes the lymphoid tyrosine phosphatase (LYP) and is the second strongest non-HLA genetic risk factor for type 1 diabetes. The PTPN22 susceptibility allele generates an LYP variant with an arginine-to-tryptophan substitution at position 620 (R620W) that has been reported by several studies to impart a gain of function. However, a recent report investigating both human cells and a knockin mouse model containing the R620W homolog suggested that this variation causes faster protein degradation. Whether LYP R620W is a gain- or loss-of-function variant, therefore, remains controversial. To address this issue, we generated transgenic NOD mice (nonobese diabetic) in which Ptpn22 can be inducibly silenced by RNA interference. We found that Ptpn22 silencing in the NOD model replicated many of the phenotypes observed in C57BL/6 Ptpn22 knockout mice, including an increase in regulatory T cells. Notably, loss of Ptpn22 led to phenotypic changes in B cells opposite to those reported for the human susceptibility allele. Furthermore, Ptpn22 knockdown did not increase the risk of autoimmune diabetes but, rather, conferred protection from disease. Overall, to our knowledge, this is the first functional study of Ptpn22 within a model of type 1 diabetes, and the data do not support a loss of function for the PTPN22 disease variant.Publication The autoimmunity-associated gene RGS1 affects the frequency of T follicular helper cells(2016) Caballero-Franco, Celia; Kissler, StephanRGS1 (regulator of G-protein signaling 1) has been associated with multiple autoimmune disorders including type 1 diabetes. RGS1 desensitizes the chemokine receptors CCR7 and CXCR4 that are critical to the localization of T and B cells in lymphoid organs. To explore how RGS1 variation contributes to autoimmunity, we generated Rgs1 knockdown (KD) mice in the nonobese diabetic (NOD) model for type 1 diabetes. We found that Rgs1 KD increased the size of germinal centers, but decreased the frequency of T follicular helper (TFH) cells. We show that loss of Rgs1 in T cells had both a T cell-intrinsic effect on migration and TFH cell frequency, and an indirect effect on B cell migration and germinal center formation. Notably, several recent publications described an increase in circulating TFH cells in patients with type 1 diabetes, suggesting this cell population is involved in pathogenesis. Though Rgs1 KD was insufficient to alter diabetes frequency in the NOD model, our findings raise the possibility that RGS1 plays a role in autoimmunity owing to its function in TFH cells. This mechanistic link, while speculative at this time, would lend support to the notion that TFH cells are key participants in autoimmunity and could explain RGS1’s association with several immune-mediated diseases.Publication Genome-Scale in Vivo CRISPR Screen Identifies RNLS as a Target for Beta Cell Protection in Type 1 Diabetes(Springer Science and Business Media LLC, 2020-07-27) Cai, Erica P.; Ishikawa, Yuki; Zhang, Wei; de Carvalho Leite, Nayara; Li, Jian; Hou, Shurong; Kiaf, Badr; Hollister-Lock, Jennifer; Yilmaz, Nese Kurt; Schiffer, Celia A.; Melton, Douglas; Kissler, Stephan; Yi, PengType 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta cells. Pluripotent stem cells can now be differentiated into beta cells, raising the prospect of a cell replacement therapy for T1D. However, autoimmunity would rapidly destroy newly transplanted beta cells. Using a genome-scale CRISPR screen in a mouse model for T1D, here we show that deleting RNLS, a GWAS candidate gene for T1D, made beta cells resistant to autoimmune killing. Structure-based modeling identified the FDA-approved drug pargyline as a potential RNLS inhibitor. Oral pargyline treatment protected transplanted beta cells in diabetic mice, leading to disease reversal. Further, pargyline could prevent or delay diabetes onset in several mouse models for T1D. Our results identify RNLS as a modifier of beta cell vulnerability and as a potential therapeutic target to avert beta cell loss in T1D.Publication Increased β-Cell Proliferation Before Immune Cell Invasion Prevents Progression of Type 1 Diabetes(Springer Science and Business Media LLC, 2019-05-06) Dirice, Ercument; Kahraman, Sevim; De Jesus, Dario F.; El Ouaamari, Abdelfattah; Basile, Giorgio; Baker, Rocky L.; Yigit, Burcu; Piehowski, Paul D.; Kim, Mi-Jeong; Dwyer, Alexander J.; Ng, Raymond; Schuster, Cornelia; Vethe, Heidrun; Martinov, Tijana; Ishikawa, Yuki; Teo, Adrian Kee Keong; Smith, Richard D.; Hu, Jiang; Haskins, Kathryn; Serwold, Thomas; Qian, Wei-Jun; Fife, Brian T.; Kissler, Stephan; Kulkarni, RohitType 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total loss of β-cells1. Restoration of insulin-producing β-cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D2–4. Here we report that enhancing β-cell mass early in life, in two models of female NOD mice, results in immunomodulation of T-cells, reduced islet infiltration and lower β-cell apoptosis, that together protect them from developing T1D. The animals displayed altered β-cell antigens, and islet transplantation studies showed prolonged graft survival in the NOD-LIRKO model. Adoptive transfer of splenocytes from the NOD-LIRKOs prevented development of diabetes in pre-diabetic NOD mice. A significant increase in the splenic CD4+CD25+FoxP3+ regulatory T-cell (Treg) population was observed to underlie the protected phenotype since Treg depletion rendered NOD-LIRKO mice diabetic. The increase in Tregs coupled with activation of TGF-β/SMAD3 signaling pathway in pathogenic T-cells favored reduced ability to kill β-cells. These data support a previously unidentified observation that initiating β-cell proliferation, alone, prior to islet infiltration by immune cells alters the identity of β-cells, decreases pathologic self-reactivity of effector cells and increases Tregs to prevent progression of T1D.