Monocytes in Type 1 diabetes families exhibit high cytolytic activity and subset abundances that correlate with clinical progression

Monocytes are immune regulators implicated in the pathogenesis of Type 1 diabetes (T1D), an autoimmune disease that targets the insulin-producing pancreatic β-cell. We determined that monocytes of recent onset (RO) T1D patients and their healthy siblings express proinflammatory/cytolytic transcriptomes and hyper-secrete cytokines in response to lipopolysaccharide exposure compared to unrelated healthy controls (uHC). Flow cytometry measured elevated circulating abundances of intermediate monocytes and >2-fold more CD14+CD16+HLADR+KLRD1+PRF1+ NK-like monocytes among ROT1D patients compared to uHC. The intermediate to nonclassical monocyte ratio among ROT1D patients correlated with the decline in functional β-cell mass during the first 24 months post-onset. Among sibling non-progressors, flow cytometry measured temporal decreases in the intermediate to nonclassical monocyte ratio and NK-like monocyte abundances; these changes coincided with increases in peripheral activated regulatory T-cells. In contrast, these monocyte populations exhibited stability among T1D progressors. This study associates heightened monocyte proinflammatory/cytolytic activity with T1D susceptibility and progression and offers insight to the age-dependent decline in T1D susceptibility. RNA was extracted from monocytes negatively selected from PBMC of 4 groups. 14 ROT1D samples were collected from subjects collected 2–7 months after diagnosis from subjects with histories of good glycemic control and possessed ≥1 autoantibody. Healthy control subjects were free of known infection at sample collection and belonged to one of the following 3 groups: 1) 15 HRSs - autoantibody-negative siblings of probands with high-risk (DR3 and/or DR4) HLA genotypes (HRS); 2) 19 LRSs - autoantibody-negative siblings of probands with lower risk (non-DR3/DR4) HLA genotypes (LRS); and 3) 14 uHCs - possessing no family history of T1D (uHC).