Single-cell immune transcriptomics reveals an inflammatory–inhibitory set-point spectrum in autoimmune diabetes

Autoimmune diabetes encompasses rapidly progressive type 1 diabetes mellitus (T1D) and indolent latent autoimmune diabetes in adults (LADA), which represent distinct inflammatory set points along a shared autoimmune spectrum. Yet, the immunological mechanisms that determine these divergent inflammatory states remain unresolved. We performed single-cell RNA sequencing with paired T and B cell receptor profiling on over 400,000 PBMCs from patients with LADA, newly diagnosed T1D, and individuals acting as 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-κB, EGFR, MAPK, and hypoxia pathways, coupled with a TNF-centered communication hub, enhanced MHC signaling, disrupted adhesion, and promoted systemic inflammation. LADA, by contrast, exhibited global suppression of NF-κB/EGFR activity, retention of moderate JAK/STAT tone, reinforced NK 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 multiclonal, patient-unique adaptive repertoires, emphasizing the primacy of signaling context over receptor convergence. These findings define autoimmune diabetes as an inflammatory-inhibitory set-point continuum, positioning the NF-κB/EGFR-JAK/STAT gradient and HLA-C-KIR axis as potential therapeutic targets to preserve residual β cell function.

Citation

Golodnikov, I.I., Podshivalova, E.S., Chechekhin, V.I., Zubritskiy, A.V., Matrosova, A.A., Sergeev, N.A., Samsonova, M.D., Dvoryanchikov, Y.V., Nikonova, T.V., Bondarenko, E.V., Loguinova, M.Y., Medvedeva, Y.A., Laptev, D.N., Khusainova, R.I., Minniakhmetov, I.R., Shestakova, M.V., Mokrysheva, N.G., Dedov, I.I. (2026). Single-cell immune transcriptomics reveals an inflammatory–inhibitory set-point spectrum in autoimmune diabetes. JCI Insight, 11(1). https://doi.org/10.1172/jci.insight.199050

Source

JCI Insight

Keywords

32 Biomedical and Clinical Sciences, 3202 Clinical Sciences, 3204 Immunology, Adult, CD8-Positive T-Lymphocytes, Diabetes Mellitus, Type 1, Female, Humans, Inflammation, Killer Cells, Natural, Latent Autoimmune Diabetes in Adults, Leukocytes, Mononuclear, Male, Middle Aged, NF-kappa B, Signal Transduction, Single-Cell Analysis, Transcriptome, 3 Good Health and Well Being

Publisher

American Society for Clinical Investigation

DOI

10.1172/jci.insight.199050

Additional links

https://insight.jci.org/articles/view/199050/