Insulin Receptor–Expressing T Cells Appear in Individuals at Risk for Type 1 Diabetes and Can Move into the Pancreas in C57BL/6 Transgenic Mice

• Published in: The Journal of immunology (1950) Vol. 206; no. 7; pp. 1443 - 1453
• Main Authors: Nandedkar-Kulkarni, Neha, Esakov, Emily, Gregg, Brigid, Atkinson, Mark A, Rogers, Douglas G, Horner, James D, Singer, Kanakadurga, Lundy, Steven K, Felton, Jamie L, Al-Huniti, Tasneem, Kalinoski, Andrea Nestor, Morran, Michael P, Gupta, Nirdesh K, Bretz, James D, Balaji, Swapnaa, Chen, Tian, McInerney, Marcia F
• Format: Journal Article
• Language: English
• Published: United States 01.04.2021
• Subjects: Adolescent; Adult; Animals; Cell Movement; Child; Diabetes Mellitus, Type 1 - immunology; Disease Models, Animal; Female; Humans; Insulin-Secreting Cells - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Transgenic; Pancreas - immunology; Receptor, Insulin - metabolism; Risk; T-Lymphocytes - immunology; Young Adult
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1900357

Insulin receptor (IR) expression on the T cell surface can indicate an activated state; however, the IR is also chemotactic, enabling T cells with high IR expression to physically move toward insulin. In humans with type 1 diabetes (T1D) and the NOD mouse model, a T cell–mediated autoimmune destruction of insulin-producing pancreatic β cells occurs. In previous work, when purified IR+ and IR− T cells were sorted from diabetic NOD mice and transferred into irradiated nondiabetic NOD mice, only those that received IR+ T cells developed insulitis and diabetes. In this study, peripheral blood samples from individuals with T1D (new onset to 14 y of duration), relatives at high-risk for T1D, defined by positivity for islet autoantibodies, and healthy controls were examined for frequency of IR+ T cells. High-risk individuals had significantly higher numbers of IR+ T cells as compared with those with T1D (p < 0.01) and controls (p < 0.001); however, the percentage of IR+ T cells in circulation did not differ significantly between T1D and control subjects. With the hypothesis that IR+ T cells traffic to the pancreas in T1D, we developed a (to our knowledge) novel mouse model exhibiting a FLAG-tagged mouse IR on T cells on the C57BL/6 background, which is not susceptible to developing T1D. Interestingly, these C57BL/6-CD3FLAGmIR/mfm mice showed evidence of increased IR+ T cell trafficking into the islets compared with C57BL/6 controls (p < 0.001). This transgenic animal model provides a (to our knowledge) novel platform for investigating the influence of IR expression on T cell trafficking and the development of insulitis.