Human immune phenotyping reveals accelerated aging in type 1 diabetes

Abstract

The composition of immune cells in peripheral blood is dramatically remodeled throughout the human lifespan, as environmental exposures shape the proportion and phenotype of cellular subsets. These dynamic shifts complicate efforts to identify disease-associated immune signatures in type 1 diabetes (T1D), which is variable in age of onset and rate of beta-cell decline. Herein, we conducted standardized flow cytometric immune profiling on peripheral blood from a cross-sectional cohort of T1D participants (n=240), their first-degree relatives (REL, n=310), those at increased risk with two or more islet autoantibodies (RSK, n=24), and autoantibody negative healthy controls (CTR, n=252). We constructed an immune-age predictive model in healthy subjects and developed an interactive data visualization portal (ImmScape; https://ufdiabetes.shinyapps.io/ImmScape/). When applied to the T1D cohort, this model revealed accelerated immune aging (p<0.001) as well as phenotypic signatures of disease after age correction. Of 192 investigated flow cytometry and complete blood count readouts, 46 were significantly associated with age only, 25 with T1D only, and 23 with both age and T1D. Phenotypes associated with T1D after age-correction were predictive of T1D status (AUROC=82.3%). Phenotypes associated with accelerated aging in T1D included increased CXCR3+ and PD-1+ frequencies in naive and memory T cell subsets, despite reduced PD-1 expression levels (mean fluorescence intensity) on memory T cells. Additionally, quantitative trait locus analysis linked an increase in HLA-DR expression on monocytes with the T1D-associated HLA-DR4/DQ8 genotype, regardless of clinical group. Our findings demonstrate advanced immune aging in T1D and highlight disease-associated phenotypes for biomarker monitoring and therapeutic interventions.

Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset

“…Therefore, profiling the immune system in individuals with high genetic risk may uncover immune perturbations associated with T1D disease susceptibility. Using the HLA portion of Genetic Risk Score 2 (GRS2) 68 , we generated an HLA genetic risk score (HLA-GRS) that accounts for HLA DR-DQ haplotype interactions 17,68 , with a higher score indicating a higher risk for disease development. As expected, T1D donors had increased HLA-GRS compared to ND (Figure 7A).…”

“…As T1D progresses, β cell destruction is thought to accelerate along with proinflammatory signaling, peaking at T1D onset. Long-term inflammation drives immune aging, activation, and differentiation signatures in PBMCs of T1D donors 17 . We found that these immune activation-associated changes also occur in pLN and mLN of T1D donors.…”

Combination treatment of a novel CXCR3 antagonist ACT-777991 with an anti-CD3 antibody synergistically increases persistent remission in experimental models of type 1 diabetes

“…CXCR3 has been described to be responsible for T-cell migration to inflamed tissue along a CXCR3 ligand-concentration gradient [ 34–36 ]. Specifically, CXCR3 was shown to be increased on various T-cell subsets in patients with type 1 diabetes, including naïve and EM CD8 + T-cells and follicular T helper cells [ 28 ]. Given that aCD3 treatment increased the relative proportion of circulating CD8 + T cells ( Fig.…”

“…This effect could explain the transient effect of aCD3 monotherapy and, depending on the degree of escape, also the lack of response in a subgroup of patients. Even if CXCR3 was shown to be increased on various T-cell subsets in patients with type 1 diabetes, thus potentially having a detrimental effect on disease progression [ 28 ], some studies have reported reduced CXCR3 expression on blood T cells in individuals with long-lasting type 1 diabetes [ 39 ]. The conflicting results may rely on various factors such as differences in disease stages and methodologies used for CXCR3 expression assessment.…”

“…CXCR3 is increased on various T-cell subsets in patients with type 1 diabetes, including effector memory CD8 + T cells [ 28 ]. Given that aCD3 treatment induces transient lymphopenia affecting preferentially CD4 + vs. CD8 + T cells, both in patients with type 1 diabetes [ 13 ] and in preclinical models [ 27 ], and increases proportions of circulating antigen-experienced CD8 + T-cell subsets in patients with type 1 diabetes [ 13 ], we hypothesized that aCD3 treatment may spare CXCR3 autoreactive T cells.…”