Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

• Published in: Clinical immunology (Orlando, Fla.) Vol. 181; pp. 67 - 74
• Main Authors: Schwedhelm, Katharine, Thorpe, Jerill, Murray, Sara A., Gavin, Marc, Speake, Cate, Greenbaum, Carla, Cerosaletti, Karen, Buckner, Jane, Long, S. Alice
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2017
• Subjects: Activation; Adolescent; Adult; Allergy and Immunology; Case-Control Studies; CD4 T cell; CD4-Positive T-Lymphocytes - immunology; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 2 - immunology; Female; Humans; IL-2; In Vitro Techniques; Interleukin-2 - immunology; Lymphocyte Activation - immunology; Male; Middle Aged; Receptors, Antigen, T-Cell - immunology; Receptors, Interleukin-2 - immunology; Signal Transduction; Signaling; T-Lymphocyte Subsets - immunology; Type 1 diabetes; Young Adult; T1D; pSTAT5; T2D; Treg; CD4 T cell; IL-2; Activation; PBMC; Signaling; SNP; Type 1 diabetes; FDR; Teff; CTL; peripheral blood mononuclear cells; single nucleotide polymorphism; control; regulatory T cell; effector T cell; type 2 diabetes; phosphorylated Signal Transducer and Activator of Transcription; false discovery rate
• ISSN: 1521-6616; 1521-7035; 1521-7035
• DOI: 10.1016/j.clim.2017.06.004

The IL-2/IL-2R pathway is implicated in type 1 diabetes (T1D). While its role in regulatory T cell (Treg) biology is well characterized, mechanisms that influence IL-2 responses in effector T cells (Teff) are less well understood. We compared IL-2 responses in 95 healthy control and 98 T1D subjects. In T1D, low IL-2 responsiveness was most pronounced in memory Teff. Unlike Treg, CD25 expression did not influence the Teff responses. Reduced IL-2 responses in memory Teff were not rescued by resting, remained lower after activation and proliferation, and were absent in type 2 diabetes. Comparing basal IL-2 responses in resting versus activated cells, memory Teff displayed lower, but more sustained, responses to IL-2 overtime. These results suggest that T1D-associated defects in the Teff compartment are due to intrinsic factors related to activation. Evaluation of both Teff and Treg IL-2R signaling defects in T1D subjects may inform selection of therapies. •Low response to IL-2 is most prominent in memory CD4 Teff of T1D subjects.•Multiple factors influence T1D-associated low IL-2 response in Teff.•Low, but sustained TCR activation correlates with low basal IL-2R signaling.•Activation enhances low IL-2 responsiveness suggesting a regulated response.