Project Details
Projekt
Characterization of CD8 T cells in human Type 1 Diabetes
Applicant
Dr. Christine Bender
Subject Area
Immunology
Term
from 2017 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 329313839
Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by the specific immune destruction of insulin-producing beta cells. These cells could be identified in islets of human diabetic donors using in situ tetramer staining. CD8 T cells predominantly infiltrate insulin-containing islets, indicating that insulin is an important potential driver of autoreactivity. However, little is known about the specificity and phenotype/function of the cells present in the human pancreas in T1D. In addition, they have recently shown that CD8 T cells can be found in high numbers in the exocrine tissue in human T1D. This occurs independently of insulin presence and supports the idea that a non-specific inflammatory environment in the exocrine pancreas could contribute to T1D pathogenesis in some cases. Finally, viruses have long been considered key players in the development of T1D, but definitive proof for their presence in the pancreas during diabetogenesis is still lacking. The overall objective is to further characterize the pool of self and virus-specific CD8 T cells in the exocrine and endocrine tissue and to understand how their specificities and phenotype evolve with disease progression. Aim 1: To define the auto-antigen specificities and phenotype of CD8 T cells in the exocrine tissue in human T1D and to compare them to those found inside the islets. The goal is to systematically characterize the infiltrating autoreactive CD8 T cell population in the pancreas. I will assess numbers and activation status of autoreactive CD8 T cells by co-staining for phenotypic markers and cytokines of interest. I will study donors with short and long disease duration as well as pre-diabetic donors to determine how the specificities might change over time and with disease duration. Aim 2: To study the association of viral infection and human T1D: The goal is to assess the presence and frequency of virus-specific CD8 T cells in correlation with the histopathology of the human pancreas and hallmark signs of viral presence.2.1: To identify human CD8 T cells recognizing viral antigens in the pancreas: In this aim I will identify CD8 T cells with specificity to common viruses such as cytomegalovirus or Epstein-Barr virus and enteroviruses and compare their frequencies. The presence of virus-specific T cells at different stages of the disease may indicate a possible correlation with disease initiation and/or progression. 2.2: To correlate the presence of virus-specific T cells with the detection of viral signatures in human T1D: In this subaim I will study whether antiviral cells are present at increased frequencies in islets with pathological changes. This study will be the first to systematically characterize autoreactive CD8 T cells in situ in the human pancreas. Our work will provide critical information on the pathogenesis of human T1D and may lead to additional opportunities for novel therapies.
DFG Programme
Research Fellowships
International Connection
USA
