Human immune phenotyping reveals accelerated aging in type 1 diabetes

• Type of Material: Article
• Authors: Melanie R Shapiro, University of Florida, Gainesville, Florida; Xiaoru Dong, University of Florida, Gainesville, Florida; Daniel J Perry, University of Florida, Gainesville, Florida; James M McNichols, University of Florida, Gainesville, Florida; Puchong Thirawatananond, University of Florida, Gainesville, Florida; Amanda L Posgai, University of Florida, Gainesville, Florida; Leeana D Peters, University of Florida, Gainesville, Florida; Keshav Motwani, University of Florida, Gainesville, Florida; Richard S Musca, University of Florida, Gainesville, Florida; Andrew B. Muir, Emory University; Patrick Concannon, University of Florida, Gainesville, Florida; Laura M Jacobsen, University of Florida, Gainesville, Florida; Clayton E Mathews, University of Florida, Gainesville, Florida; Clive H Wasserfall, University of Florida, Gainesville, Florida; Michael J Haller, University of Florida, Gainesville, Florida; Desmond A Schatz, University of Florida, Gainesville, Florida; Mark A Atkinson, University of Florida, Gainesville, Florida; Maigan A Brusko, University of Florida, Gainesville, Florida; Rhonda Bacher, University of Florida, Gainesville, Florida; Todd M Brusko, University of Florida, Gainesville, Florida
• Language: English
• Date: 2023-09-08
• Publisher: The American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Shapiro et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1172/jci.insight.170767
• Title of Journal or Parent Work: JCI Insight
• Volume: 8
• Issue: 17
• Start Page: e170767
• Grant/Funding Information: Funding was provided by NIH P01 AI042288 (to MAA and TMB), NIH R01 DK106191 (to TMB), NIH Human Islet Research Network Consortium on Human Islet Biomimetics UG3/UH3 DK122638 (to TMB and CEM), The Leona M. and Harry B. Helmsley Charitable Trust 2019PG-T1D011 (to TMB), JDRF Postdoctoral Fellowship 3-PDF-2022-1137-A-N (to MRS), Diabetes Research Connection project 45 (to MRS), JDRF Postdoctoral Fellowship 2-PDF-2016-207-A-N (to DJP), NIH F30 DK128945 (to PT), NIH T32 DK108736 (to LDP), and NIH F31 DK129004 (to LDP).
• Keywords: Autoimmunity; Autoimmune diseases; disease-associated immune signatures; biomarker; Immunology; Diabetes
• Research Categories: Biology, Genetics; Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

The proportions and phenotypes of immune cell subsets in peripheral blood undergo continual and dramatic remodeling throughout the human life span, which complicates efforts to identify disease-associated immune signatures in type 1 diabetes (T1D). We conducted cross-sectional flow cytometric immune profiling on peripheral blood from 826 individuals (stage 3 T1D, their first-degree relatives, those with ≥2 islet autoantibodies, and autoantibody-negative unaffected controls). We constructed an immune age predictive model in unaffected participants and observed accelerated immune aging in T1D. We used generalized additive models for location, shape, and scale to obtain age-corrected data for flow cytometry and complete blood count readouts, which can be visualized in our interactive portal (ImmScape); 46 parameters were significantly associated with age only, 25 with T1D only, and 23 with both age and T1D. Phenotypes associated with accelerated immunological aging in T1D included increased CXCR3+ and programmed cell death 1–positive (PD-1+) frequencies in naive and memory T cell subsets, despite reduced PD-1 expression levels on memory T cells. Phenotypes associated with T1D after age correction were predictive of T1D status. Our findings demonstrate advanced immune aging in T1D and highlight disease-associated phenotypes for biomarker monitoring and therapeutic interventions.