Research Interest:

Autoimmune Type 1 Diabetes (T1D) is characterized by the progressive loss of immune tolerance, leading to the aberrant activation of autoreactive immune cells and the destruction of the insulin-producing β-cells in the pancreas. The main cellular mediators of immune tolerance are Foxp3+ regulatory T cells (Tregs), which play a crucial part in the prevention of autoimmunity. Apart from their classical tasks in taming autoimmune activation, Tregs exert key non-canonical functions in tissues, including the pancreas, to safeguard local homeostasis. We and others have shown that T1D and its pre-symptomatic phase (islet autoimmunity) are characterized by multiple layers of Treg impairments, including impairments in Treg induction, plasticity and stability. Despite these insights into the role of Tregs in regulating islet autoimmunity, little is known about β-cell-related metabolic cues including insulin receptor signaling that can regulate pancreas-residing Tregs.  

Project Title:

Functional role of T cell-specific inceptor expression in autoimmunity 

Project Description:

Recently, the insulin inhibitory receptor (inceptor) was identified as a negative regulator of insulin signaling on pancreatic β-cells and first analyses using mRNA expression profiles from the Immgen database indicate inceptor expression on T cells. However, the functional role of inceptor on T cells as well as its contribution to aberrant immune activation in autoimmunity remains to be 
determined. We have generated T cell and Treg-specific inceptor knockout (KO) mice to dissect the role of inceptor in directing Tregs vs. Th17 cells in the pancreas. First preliminary analyses point towards phenotypic alterations in pancreas-residing T cells in the absence of inceptor with an enhanced proportion of T cells harboring an effector memory phenotype in the KO mice. We will 
perform cellular and molecular analyses of CD45+ immune cells in the pancreas of inceptor KO vs. control mice. Using single-cell RNA Sequencing as well as multi-color flow cytometry we will define T cell activation and effector profiles; assess Treg subphenotypes and pancreas-specific Treg clusters together with Treg stability/plasticity. We will decipher extrinsic vs. intrinsic contributions of 
inceptor signaling in guiding β-cell – T cell crosstalk. Therefore, analysis of pancreas-specific T cell/Treg differentiation and function will be performed on CD45+ immune cells both from β-cell specific inceptor KO mice as well as from T cell and Treg-specific inceptor KO mice under steady state or proinflammatory conditions. To further link inceptor expression on T cells with autoimmunity, we will induce pancreas autoimmunity in T cell or Treg-specific inceptor KO animals by multiple low-dose injections of streptozotocin, thereby modeling T1D.  

1. Scherm MG, Serr I, Zahm AM, Schug J, et al., miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes. Nature Communications, 2019. 10(1): p. 5697 DOI: 10.1038/s41467-019-13587-3. 
2. Becker M, Serr I, Salb VK, Ott VB, et al., Short-term cold exposure supports human Treg induction in vivo. Molecular Metabolism, 2019. 28: p. 73-82 DOI: 10.1016/j.molmet.2019.08.002. 
3. Serr I, Scherm MG, Zahm AM, Schug J, et al., A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. Science Translational Medicine, 2018. 10(422): p. eaag1782 DOI: 10.1126/scitranslmed.aag1782 %J Science Translational Medicine. 
4. Kälin S, Becker M, Ott VB, Serr I, et al., A Stat6/Pten Axis Links Regulatory T Cells with Adipose Tissue Function. Cell Metabolism, 2017. 26(3): p. 475-492.e7 DOI: 10.1016/j.cmet.2017.08.008. 
5. Serr I, Furst RW, Achenbach P, Scherm MG, et al., Type 1 diabetes vaccine candidates promote human Foxp3(+)Treg induction in humanized mice. Nature Communications, 2016. 7: p. 10991 DOI: 10.1038/ncomms10991. 
6. Serr I, Furst RW, Ott VB, Scherm MG, et al., miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity. Proceedings of the National Acadamy of Sciences U S A, 2016. 113(43): p. E6659-E6668 DOI: 10.1073/pnas.1606646113. 


Biographical Sketch