Interferons limit autoantigen-specific CD8+ T-cell expansion in the non-obese diabetic mouse

• Published in: Cell reports (Cambridge) 2022-04, Vol.39 (4), p.110747-110747, Article 110747
• Main Authors: Jhala, Gaurang, Krishnamurthy, Balasubramanian, Brodnicki, Thomas C., Ge, Tingting, Akazawa, Satoru, Selck, Claudia, Trivedi, Prerak M., Pappas, Evan G., Mackin, Leanne, Principe, Nicola, Brémaud, Erwan, De George, David J., Boon, Louis, Smyth, Ian, Chee, Jonathan, Kay, Thomas W.H., Thomas, Helen E.
• Format: Article
• Language: English
• Subjects: Animals; Autoantigens; autoimmune diabetes; CD8-Positive T-Lymphocytes; Cytokines - metabolism; Diabetes Mellitus; Interferon-gamma - metabolism; interferons; Interferons - metabolism; interleukin-2; Interleukin-2 - metabolism; MHC tetramers; Mice; Mice, Inbred NOD; Suppressor of Cytokine Signaling 1 Protein - genetics; Suppressor of Cytokine Signaling 1 Protein - metabolism; Suppressor of Cytokine Signaling Proteins - metabolism; suppressor of cytokine singling 1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110747

Interferon gamma (IFNγ) is a proinflammatory cytokine implicated in autoimmune diseases. However, deficiency or neutralization of IFNγ is ineffective in reducing disease. We characterize islet antigen-specific T cells in non-obese diabetic (NOD) mice lacking all three IFN receptor genes. Diabetes is minimally affected, but at 125 days of age, antigen-specific CD8+ T cells, quantified using major histocompatibility complex class I tetramers, are present in 10-fold greater numbers in Ifngr-mutant NOD mice. T cells from Ifngr-mutant mice have increased proliferative responses to interleukin-2 (IL-2). They also have reduced phosphorylated STAT1 and its target gene, suppressor of cytokine signaling 1 (SOCS-1). IFNγ controls the expansion of antigen-specific CD8+ T cells by mechanisms which include increased SOCS-1 expression that regulates IL-2 signaling. The expanded CD8+ T cells are likely to contribute to normal diabetes progression despite reduced inflammation in Ifngr-mutant mice. [Display omitted] •NOD mice deficient in all three interferon receptors were generated using CRISPR•10-fold increased islet-specific CD8+ T cells in IFNGR-mutant mice•T cells from IFNGR-mutant mice have increased proliferative response to IL-2•Diabetes occurs in interferon-receptor-mutant mice despite reduced islet infiltration Jhala et al. find a 10-fold increase in the number of islet antigen-specific CD8+ T cells in NOD mice lacking IFNγ receptors. These cells have increased proliferative responses to IL-2. This study helps us understand the mechanistic basis of the lack of therapeutic benefits from deficiency of IFNγ in autoimmune diabetes.