Comparative Single-Cell Transcriptomics of Immune Profiles in LADA Versus Type 1 Diabetes

Autoimmune diabetes encompasses rapidly progressive type 1 diabetes mellitus (T1D) and indolent latent autoimmune diabetes in adults (LADA), yet the immunological drivers of this kinetic divergence remain unresolved. We performed single-cell RNA sequencing with paired T and B cell receptor profiling on over 400,000 peripheral blood mononuclear cells (PBMCs) from patients with LADA, newly diagnosed T1D, and healthy controls. PBMC composition was comparable across cohorts, indicating that qualitative rather than quantitative immune differences underlie disease heterogeneity. In T1D, pan-lineage activation of NF-kB, EGFR, MAPK, and hypoxia pathways, coupled with a TNF-centered communication hub, enhanced MHC signaling, and disrupted adhesion, promoted systemic inflammation. LADA, by contrast, exhibited global suppression of NF-kB/EGFR activity, retention of moderate JAK/STAT tone, reinforced natural killer cell inhibitory checkpoints via HLA-C-KIR2DL3/3DL1 interaction, and stabilized CD8+ T cell synapses through HLA-C-CD8 binding, collectively restraining effector activation. Single-cell V(D)J analysis revealed polyclonal, patient-unique adaptive repertoires, emphasizing the primacy of signaling context over receptor convergence. These findings define LADA and T1D as endpoints on an inflammatory-inhibitory spectrum and identify the NF-kB/EGFR-JAK/STAT gradient and HLA-C-KIR axis as potential therapeutic targets for preserving residual beta-cell function in autoimmune diabetes.