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ResearchIn-Press PreviewEndocrinologyGenetics Open Access | 10.1172/jci.insight.199050

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

Ivan I. Golodnikov,1 Elizaveta S. Podshivalova,1 Vadim I. Chechekhin,1 Anatoliy V. Zubritskiy,1 Alina A. Matrosova,1 Nikita A. Sergeev,1 Margarita D. Samsonova,1 Yaroslav V. Dvoryanchikov,1 Tatiana V. Nikonova,1 Ekaterina V. Bondarenko,1 Marina Yu. Loguinova,1 Yulia A. Medvedeva,1 Dmitry N. Laptev,1 Rita I. Khusainova,1 Ildar R. Minniakhmetov,1 Marina V. Shestakova,1 Natalia G. Mokrysheva,1 and Ivan I. Dedov1

1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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1Institute of Diabetes, Endocrinology Research Centre, Moscow, Russian Federation

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Published December 1, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.199050.
Copyright © 2025, Golodnikov et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 1, 2025 - Version history
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Abstract

Autoimmune diabetes encompasses rapidly progressive type 1 diabetes mellitus (T1D) and indolent latent autoimmune diabetes in adults (LADA), representing 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 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-κB, 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-κB/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 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.

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  • Version 1 (December 1, 2025): In-Press Preview
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