This study aims to investigate the role of CD45RA+CCR7+CD4 T cells in the pathogenesis of type 1 diabetes (T1D). Historically, naïve T cells were deemed irrelevant in T1D development due to their presumed lack of antigen experience. However, distinct subsets of naïve T cells with varying phenotypes and functions have been identified, with recent literature indicating that autoreactive T cells in T1D exhibit stem-like properties with phenotypes between naïve and effector/memory states.

Our data show that the enrichment of CD45RA+CCR7+CD4 T cells in the peripheral blood of newly diagnosed T1D children. Moreover, a higher frequency of this cell subset at diagnosis correlates with a poorer outcome, regardless of age. The hypothesis posits that CD45RA+CCR7+CD4 T cells form a heterogeneous pool enriched with stem-like cells possessing effector functions, actively contributing to beta cell damage and T1D development.

To investigate the heterogeneity of CD45RA+CCR7+CD4 T cells, the study will utilize single-cell RNA sequencing coupled with TCR sequencing on longitudinal blood samples from relatives of T1D patients. This approach aims to explore the phenotype and TCR repertoire, monitoring changes in plasticity and expansion of TCR clones as individuals transition through T1D stages, with special attention to stem cell memory subsets expressing CD95. Additionally, multi-color staining of pancreas sections will be performed to localize CD45RA+CCR7+CD4 T cells relative to beta cells and assess cell infiltration dynamics in different T1D stages. Pancreas tissues from non-diabetic and autoantibody-positive subjects, recent onset and long-standing T1D patients will be analyzed.

Overall, this project seeks to shed light on the potential role of CD45RA+CCR7+CD4 T cells in beta cell damage, highlighting their potential significance as overlooked players in T1D pathogenesis and contributing to the decline of beta cell function. This project is under discussion for funding from Helmsley Charitable Trust.