Cytokine signatures in human (pre-)diabetic pancreas
Final Report Abstract
We wished to explore the impact of anti-inflammatory cytokines IL4 and IL10 on a dynamic in vitro model of human T1D. Human islet microtissues and pancreatic islets were exposed to either a proinflammatory cytokine cocktail alone; activated and partially HLA-matched PBMC alone; or both. This resulted in an immune attack against the islet with a functional decline of beta cells, infiltration of PBMC into the islet, and an upregulation of HLA-I on beta cells (a known beta cell stress marker). To capture the dynamics of the immune attack and beta cell demise, we performed acute experiments in islets exposed to stressors for a few hours and chronic experiments in islets stressed for multiple days. Islets were preincubated with IL10 or IL4 to assess if either could protect the islets from stressor-mediated insult. Preincubation with IL4 or IL10 failed to protect the islets from loss of endocrine function assessed by GSIS. However, both cytokines successfully reduced the infiltration rates of activated T cells into the islet. They may thus protect the islet from the autoimmune attack and have beneficial effects in the context of T1D development. HLA-I expression on beta cells was upregulated in response to chronic proinflammatory cytokine-induced or PBMC-induced stress. This was not affected through preincubation with anti-inflammatory cytokines. However, HLA-I expression on beta cells was associated with infiltration of PBMC into the islets and both HLA-I expression and infiltration were associated with impaired insulin secretion. In summary, our results support the hypothesis that a loss of beta cell endocrine function intrinsically mediates an increase in the presentation of autoantigenic peptides associated with HLA-I. This may ultimately target them for CD8 T cell-mediated immune destruction.
Publications
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“Peripheral autoreactive CD8 T-cell frequencies are too variable to be a reliable predictor of disease progression of human type 1 diabetes”, Clin Transl Immunology. 2021 Jul 11;10(7):e1309
Wesley JD, Pfeiffer S, Schneider D, Friedrich D, Perdue N, Sehested-Hansen B, Hagopian W, von Herrath MG
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“Upregulation of HLA class II in pancreatic beta cells from organ donors with type 1 diabetes”, Diabetologia. 2022 Feb;65(2):387-401
Quesada-Masachs E, Zilberman S, Rajendran S, Chu T, McArdle S, Kiosses WB, Lee JM, Yesildag B, Benkahla MA, Pawlowska A, Graef M, Pfeiffer S, Mikulski Z, von Herrath M
