Immune context governs stage-specific responses to depleting anti-PD-1 antibody in type 1 diabetes

A depleting anti-PD-1 antibody (D-αPD-1) exhibits stage-dependent effects: delaying hyperglycemia onset in a murine early insulitis (E-insulitis) model but accelerating disease in late insulitis (L-insulitis). Compared with E-insulitis, L-insulitis pancreatic islets show elevated immune cell infiltration, a pronounced T_eff/Treg imbalance, and enrichment of proinflammatory macrophages-features that partially mirror human type 1 diabetes (T1D) pathology. D-αPD-1 treatment reduces PD-1⁺ T cells during E-insulitis but unexpectedly expands this population during L-insulitis, inconsistent with its intended depleting function. Islet macrophages, particularly the Mac3 subset, are the primary mediators of therapeutic outcomes in L-insulitis, showing enhanced islet accumulation, increased Fcγ receptor (FcγR) expression, and activation of IFN-α/γ and TNF-α response following D-αPD-1 treatment. Importantly, macrophage depletion neutralizes the hyperglycemia-accelerating effect of D-αPD-1 in L-insulitis. Collectively, proinflammatory macrophages and their interactions with D-αPD-1 critically determine antibody's therapeutic outcomes in T1D, highlighting the importance of considering macrophage-centered immune context when designing and applying such therapeutics.