Title: Identifying a signature for islet-specific IL-10 secreting (ISIS) Tregs
Funder: Juvenile Diabetes Research Foundation

Abstract: There is now strong evidence that T1D results from a failure of the immune system to control immune responses against beta cells. Regulatory T cells (Tregs) are a key component of this control. There is therefore great interest in trying to harness their activity for cure and prevention. This could be achieved via increasing Treg number or strength in individuals with, or at risk of developing T1D. Tregs come in many different forms: but the holy grail is exploit those that are activated to regulate when they encounter beta cells (we term these islet-specific Tregs). This would maximise the potency of the approach, as well as avoiding unwanted side effects, such as generalized immunosuppression. To date, islet-specific Tregs have been relatively poorly studied in human T1D.Recently, we identified a population of islet-specific Tregs we termed ISIS (Islet Specific IL-10 Secreting). IL-10 is an anti-inflammatory chemical mediator. We have shown that ISIS cells are selectively enriched in individuals who show a relative level of protection from disease; for example, adult patients with late-onset T1D and siblings of T1D patients (specifically those who lack islet cell autoantibodies and are designated low-risk). Others have added to this knowledge, showing expansion of ISIS-like responses in T1D patients entering the honeymoon period after diagnosis, when insulin needs reduce dramatically.Because of these interesting features, we have isolated ISIS cells, grown them in abundance in the laboratory and shown that they are potent Tregs, switched on by encounter with beta cell antigens and capable of suppressing inflammatory immune responses. Taken together, these findings suggest that ISIS cells play a role in disease development and that they offer a major opportunity for strengthening immune regulation. However, if we are to harness the potential of ISIS T cells in prevention studies there are key questions that need to be answered about this cell type including:(i) what is the best way to identify ISIS Tregs?(ii) are ISIS cells that we observe in individuals with new onset-T1D comparable to those without T1D?(iii) how are these cells generated in the body and are they related to the T cells that are responsible for destroying islet beta cells?(iv) what is the best way to generate ISIS T cells for immunotherapy?This project aims to address these questions through a comprehensive study of ISIS T cells isolated from individuals with and without T1D to identify a molecular signature of ISIS and pinpoint the defining features of this important cell type. This will help us understand the role of different populations of islet-specific T cells in islet destruction, identify more accurate markers of islet-specific immune regulation for use in clinical trial monitoring and may reveal better ways to increase the number of ISIS T cells in individuals with or at risk of developing T1D, with the goal of disease cure and prevention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE