Novel Molecular Signatures of Peripheral Regulatory T Cells in Kidney Disease Associated with Type 1 Diabetes

Key Points. Regulatory T cells (Tregs) from people (control, type 1 diabetes with and without albuminuria) were profiled for phenotypic and transcriptomic changes. Central memory Tregs were reduced, while Treg EMRA+ cells were higher in type 1 diabetes with albuminuria. In silico findings suggest potential interactions between Treg ligand and kidney cell receptor at transcript level. Background. Diabetic kidney disease (DKD) is a common complication of type 1 diabetes (T1D). T1D and some kidney disorders are often associated with abnormalities in regulatory T cells (Tregs). However, it is unknown if Treg subsets and their molecular architecture are altered during the onset and progression of DKD in T1D. Methods. We addressed this critical knowledge gap by characterizing changes in Tregs isolated from 31 participants (10 control, 13 with T1D, and eight T1D with albuminuria) using flow cytometry, RNA-sequencing, and microRNA profiling. Results. We identified that the effector and central memory Tregs were significantly different between groups. Similarly, multiple gene transcripts were also significantly different between groups that also overlapped with other publicly available datasets. Machine learning–based data analyses discovered a set of important microRNAs associated with clinical eGFR values. Importantly, our analyses identified two differentially expressed Treg ligand genes (leucine rich repeat containing 4B, transglutaminase-2), which interacted with the receptors on kidney cells (protein tyrosine phosphatase receptor type D/F/S, Adhesion G Protein-Coupled Receptor G1; a.k.a GPR56) in silico, providing potential mechanistic insights into the role of Tregs in DKD progression. Conclusions. Together, our work supports the yet unappreciated role of Tregs in DKD and opens new research avenues to further consolidate their causal relationship.