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 insulin-producing pancreatic beta cells. We determined that monocytes of recent onset (RO) T1D patients and their healthy siblings express proinflammatory/cytolytic transcriptomes and hypersecrete cytokines in response to lipopolysaccharide exposure compared to unrelated healthy controls (uHCs). Flow cytometry measured elevated circulating abundances of intermediate monocytes and >2-fold more CD14+CD16+HLADR+KLRD1+PRF1(+ )NK-like monocytes among patients with ROT1D compared to uHC. The intermediate to nonclassical monocyte ratio among ROT1D patients correlated with the decline in functional beta cell mass during the first 24 months after onset. Among sibling nonprogressors, temporal decreases were measured in the intermediate to nonclassical monocyte ratio and NK-like monocyte abundances; these changes coincided with increases in 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.