Wednesday, April 2, 2025
4/2/2025
Specificity, Phenotype and Function of Pancreatic CD8 T Cells in Human Type 1 Diabetes - Title: Specificity, Phenotype and Function of Pancreatic CD8 T Cells in Human Type 1 Diabetes Project Summary Human type 1 diabetes (T1D) is characterized by the immune-mediated destruction of insulin-producing pan- creatic beta cells. CD8 T cells are the most common cell found in insulitis lesions and are the principal T cell type implicated in beta cell destruction. Insulin and its precursors have been identified as key autoantigens in humans and mice due to their local abundance. The previous funding cycles for this grant have enabled us to lead the field of human islet cell investigation in T1D. Using samples from the national pancreatic organ donor consortium (nPOD) we have detected, precisely quantified, and identified the exact location of autoreactive pre-proinsulin (PPI) specific CD8 lymphocytes within the pancreata of human donors. Studies performed within this project have already revealed significant and novel findings. We first identified auto-reactive CD8 T cells in the islets of patients with T1D using a specially designed method of tetramer staining. We found that their frequency is high and likely the most predominant autoreactive cell type (1), a finding which has been inde- pendently confirmed with other methods by Nakayama et al. (2). More recently (3) we defined the precise location of these cells within a pseudo-timeline of disease development and concluded that PPI cytotoxic T lymphocytes (CTL) are already present in healthy pancreata and appear to become 'attracted' to islets during the development of T1D. This seminal observation indicates that the islets appear to expose themselves to immune recognition, and thus become a key culprit in driving T1D development. A new key development of this grant is the Orion (Rarecyte) technology that allows for highly multiplexed studies in whole tissue sec- tions, combined with state-of-the-art analysis software. The study of the whole section and multiple targets simultaneously allows to define the islet/immune interface and the communication between PPI CTL and other immune cells more precisely and with a much reduced number of samples. The present proposal will define the precise location and function of these interactions, and corroborate these findings in highly innova- tive human islet microtissues and living donor pancreatic tissue slices using dynamic in vitro models. Finally, this proposal will decipher mechanistically how some aspects of the islet immune interface can be reset/restored by the action of GLP1 agonists, building on our recent work which has shown that this drug class can maintain beta cell function (glucose-induced insulin secretion) in vitro and in vivo during the devel- opment of T1D (4). Overall, our findings should give us an unprecedented and unique understanding of how and why T1D develops, and provide mechanistic information using our novel in vitro systems, thus ultimately aiding the development of new therapeutic options.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).