Single cell resolution immune and T and B cell receptor profiling in children at high risk for type 1 diabetes

• Applicant: Professor Ezio Bonifacio, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Pediatric and Adolescent Medicine ; Rheumatology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418078457

The first years of life are critical for the development of pre-symptomatic type 1 diabetes defined by the appearance of islet autoantibodies. Early infections are relevant to this process. We propose that the monitoring of new infections in early childhood may be achieved through the tracking of memory T cell receptor and B cell receptor clonotypes that appear in the blood and that long-lasting changes to innate immune cells caused by infections may be a mechanism by which they increase susceptibility to pre-symptomatic type 1 diabetes. We have access to rare samples from the first years of life in children who have been followed to pre-symptomatic type 1 diabetes with detailed information on reported infections, and we have recently started a clinical trial of intranasal insulin treatment that allows tracking of changes before and after treatment with intranasal insulin. Using this material, we will perform single cell RNAseq on relevant immune cell populations at age 6 months and before and after the development of pre-symptomatic type 1 diabetes and before and after intranasal insulin treatment.The overall objective is to define immune changes in early childhood that associate with the development of autoimmunity seen in the pre-symptomatic phase of type 1 diabetes. Specifically, the project will:1. Identify the memory T and B cell responses in infancy through repertoires at age 6 months and correlate these to future pre-symptomatic type 1 diabetes.2. Identify innate immune signatures that precede the autoimmune stage of type 1 diabetes.3. Relate changes in memory T and B cell repertoires to autoimmune seroconversion.4. Using intranasal insulin vaccination as a model, annotate changes in memory T cell repertoire and phenotype after exposure to autoantigen.5. Build a TCR map with information gathered from (auto)antigen peptide-responsive memory T cells.

• DFG Programme: Research Grants
• Co-Investigators: Dr. Yannick F. Fuchs; Virag Sharma, Ph.D.