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Browsing by Author "Singer, Kanakadurga"
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Item CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity(Society for Leukocyte Biology, 2016-06) Morris, David L.; Oatmen, Kelsie E.; Mergian, Taleen A.; Cho, Kae Won; DelProposto, Jennifer L.; Singer, Kanakadurga; Evans-Molina, Carmella; O’Rourke, Robert W.; Lumeng, Carey N.; Medicine, School of MedicineObesity activates both innate and adaptive immune responses in adipose tissue, but the mechanisms critical for regulating these responses remain unknown. CD40/CD40L signaling provides bidirectional costimulatory signals between antigen-presenting cells and CD4(+) T cells, and CD40L expression is increased in obese humans. Therefore, we examined the contribution of CD40 to the progression of obesity-induced inflammation in mice. CD40 was highly expressed on adipose tissue macrophages in mice, and CD40/CD40L signaling promoted the expression of antigen-presenting cell markers in adipose tissue macrophages. When fed a high fat diet, Cd40-deficient mice had reduced accumulation of conventional CD4(+) T cells (Tconv: CD3(+)CD4(+)Foxp3(-)) in visceral fat compared with wild-type mice. By contrast, the number of regulatory CD4(+) T cells (Treg: CD3(+)CD4(+)Foxp3(+)) in lean and obese fat was similar between wild-type and knockout mice. Adipose tissue macrophage content and inflammatory gene expression in fat did not differ between obese wild-type and knockout mice; however, major histocompatibility complex class II and CD86 expression on adipose tissue macrophages was reduced in visceral fat from knockout mice. Similar results were observed in chimeric mice with hematopoietic Cd40-deficiency. Nonetheless, neither whole body nor hematopoietic disruption of CD40 ameliorated obesity-induced insulin resistance in mice. In human adipose tissue, CD40 expression was positively correlated with CD80 and CD86 expression in obese patients with type 2 diabetes. These findings indicate that CD40 signaling in adipose tissue macrophages regulates major histocompatibility complex class II and CD86 expression to control the expansion of CD4(+) T cells; however, this is largely dispensable for the development of obesity-induced inflammation and insulin resistance in mice.Item Doris Duke Charitable Foundation Fund to Retain Clinical Scientists: innovating support for early-career family caregivers(American Society for Clinical Investigation, 2022-12-01) Jagsi, Reshma; Beeland, T. DeLene; Sia, Kevin; Szczygiel, Lauren A.; Allen, Matthew R.; Arora, Vineet M.; Bair-Merritt, Megan; Bauman, Melissa D.; Bogner, Hillary R.; Daumit, Gail; Davis, Esa; Fagerlin, Angela; Ford, Daniel E.; Gbadegesin, Rasheed; Griendling, Kathy; Hartmann, Katherine; Hedayati, S. Susan; Jackson, Rebecca D.; Matulevicius, Susan; Mugavero, Michael J.; Nehl, Eric J.; Neogi, Tuhina; Regensteiner, Judith G.; Rubin, Michael A.; Rubio, Doris; Singer, Kanakadurga; Tucker Edmonds, Brownsyne; Volerman, Anna; Laney, Sandra; Patton, Carrie; Escobar Alvarez, Sindy; Anatomy, Cell Biology and Physiology, School of MedicineItem Insulin Receptor-Expressing T Cells Appear in Individuals at Risk for Type 1 Diabetes and Can Move into the Pancreas in C57BL/6 Transgenic Mice(American Association of Immunologists, 2021) Nandedkar-Kulkarni, Neha; Esakov, Emily; Gregg, Brigid; Atkinson, Mark A.; Rogers, Douglas G.; Horner, James D.; Singer, Kanakadurga; Lundy, Steven K.; Felton, Jamie L.; Al-Huniti, Tasneem; Kalinoski, Andrea Nestor; Morran, Michael P.; Gupta, Nirdesh K.; Bretz, James D.; Balaji, Swapnaa; Chen, Tian; McInerney, Marcia F.; Pediatrics, School of MedicineInsulin receptor (IR) expression on the T cell surface can indicate an activated state; however, the IR is also chemotactic, enabling T cells with high IR expression to physically move toward insulin. In humans with type 1 diabetes (T1D) and the NOD mouse model, a T cell-mediated autoimmune destruction of insulin-producing pancreatic β cells occurs. In previous work, when purified IR+ and IR- T cells were sorted from diabetic NOD mice and transferred into irradiated nondiabetic NOD mice, only those that received IR+ T cells developed insulitis and diabetes. In this study, peripheral blood samples from individuals with T1D (new onset to 14 y of duration), relatives at high-risk for T1D, defined by positivity for islet autoantibodies, and healthy controls were examined for frequency of IR+ T cells. High-risk individuals had significantly higher numbers of IR+ T cells as compared with those with T1D (p < 0.01) and controls (p < 0.001); however, the percentage of IR+ T cells in circulation did not differ significantly between T1D and control subjects. With the hypothesis that IR+ T cells traffic to the pancreas in T1D, we developed a (to our knowledge) novel mouse model exhibiting a FLAG-tagged mouse IR on T cells on the C57BL/6 background, which is not susceptible to developing T1D. Interestingly, these C57BL/6-CD3FLAGmIR/mfm mice showed evidence of increased IR+ T cell trafficking into the islets compared with C57BL/6 controls (p < 0.001). This transgenic animal model provides a (to our knowledge) novel platform for investigating the influence of IR expression on T cell trafficking and the development of insulitis.Item Sustaining the Pediatric Endocrinology Workforce: Recommendations from the Pediatric Endocrine Society Workforce Task Force(Elsevier, 2021-06) Allen, David B.; Aye, Tandy; Boney, Charlotte M.; Eugster, Erica A.; Misra, Madhusmita; Singer, Kanakadurga; Stafford, Diane; Witchel, Selma F.; Zeitler, Philip; Pediatrics, School of Medicine