2. Academic Validation
  3. IL-21 mediates crosstalk between T cells and NK cells during the remission of type 1 diabetes

IL-21 mediates crosstalk between T cells and NK cells during the remission of type 1 diabetes

  • Nat Metab. 2026 Jan;8(1):177-195. doi: 10.1038/s42255-025-01439-y.
Kang Lei # 1,  Xinyu Li # 1,  Ting Zhong # 1,  Rong Tang 1,  Qiaolin Deng 2,  Paul E Love 3,  Zhiguang Zhou 1,  Bin Zhao 4 5 6,  Xia Li 7
Affiliations

Affiliations

  • 1 National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China.
  • 2 Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden.
  • 3 Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • 4 National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China. [email protected].
  • 5 CSU-Sinocare Research Center for Nutrition and Metabolic Health, Xiangya School of Public Health, Central South University, Changsha, China. [email protected].
  • 6 Furong Laboratory, Changsha, China. [email protected].
  • 7 National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China. [email protected].
  • # Contributed equally.
PMID: 41566069 DOI: 10.1038/s42255-025-01439-y
Abstract

The innate immune system is increasingly recognized as a contributor to the development of type 1 diabetes (T1D), but the role of natural killer (NK) cells remains largely unclear. Here, we identify an expanded subset of transcriptionally active CD226+CD56dimCD16+ NK cells at the onset of T1D that contracts in remission. Using single-cell RNA Sequencing integrated with cross-sectional and longitudinal analyses in patients with T1D, we show that CD226+ NK cell frequency correlates with disease progression. CD226+ NK cells exhibit enhanced cytotoxicity, inflammation and glucose metabolism. Mechanistically, CD161+CD4+ T cells promote pathogenic NK cell generation through interleukin-21 (IL-21) and mTOR signalling. Inhibition of this pathway by CD226 blockade, IL-21 receptor fusion protein, IL-21 knockout or mTOR inhibition attenuates NK cell activation, reduces pancreatic infiltration and delays diabetes onset in female mice. Our data reveal a mechanistic link, bridging adaptive and innate immunity, in the progression and remission of T1D that could potentially be exploited in T1D immunotherapy.

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