Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function

Abstract

Genetic variation in the IL-7 receptor-α ( IL-7R ) gene is associated with susceptibility to human type 1 diabetes (T1D). Here we investigate the therapeutic efficacy and mechanism of IL-7Rα antibody in a mouse model of T1D. IL-7Rα antibody induces durable, complete remission in newly onset diabetic mice after only two to three injections. IL-7 increases, whereas IL-7Rα antibody therapy reduces, the IFN-γ–producing CD4 + (T H 1) and IFN-γ–producing CD8 + T cells. Conversely, IL-7 decreases and IL-7Rα antibody enhances the inhibitory receptor Programmed Death 1 (PD-1) expression in the effector T cells. Programmed Death 1 blockade reversed the immune tolerance mediated by the IL-7Rα antibody therapy. Furthermore, IL-7Rα antibody therapy increases the frequency of regulatory T cells without affecting their suppressor activity. The durable efficacy and the multipronged tolerogenic mechanisms of IL-7Rα antibody therapy suggest a unique disease-modifying approach to T1D.

IL-7 receptor α blockade, an off-switch for autoreactive T cells

“…The importance of IL-7 in the development of autoimmune disorders is further underlined by observations from genome-wide association studies that identified genetic variations of the IL-7Rα chain as risk factors for the development of T1D and multiple sclerosis (11,12). Lee et al (2) and Penaranda et al (3) have now determined the therapeutic implications of these findings in a murine model of immune-mediated diabetes, the nonobese diabetic (NOD) mouse.…”

“…Thus, harnessing autoreactive effector T cells appears to be a central requirement for novel therapeutic approaches that are urgently needed. The studies by Lee et al (2) and Penaranda et al (3) in PNAS demonstrate that blockade of IL-7 signaling can revert recent onset diabetes by fostering the inhibitory programmed cell death 1 (PD-1) protein on diabetogenic T cells, thereby limiting their autoaggressive potential.…”

Producing GM-CSF: a unique T helper subset?

“…In fact, dysregulation of the IL-7/IL-7R axis has long been implicated in autoimmune diseases, such as type 1 diabetes, multiple sclerosis and rheumatoid arthritis [7,8]. Thus, the results from Sheng et al may now provide a mechanistic link between IL-7/STAT5-mediated signaling and T helper cell-mediated pathogenicity.…”

Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis

“…17,18,24 In murine autoimmune diabetes models, the blockade of IL-7R upregulated PD-1 expression in autoreactive T cells, and the administration of recombinant IL-7 suppressed PD-1 levels. 19,20 In chronic LCMV infection, recombinant IL-7 treatment decreased PD-1 expression and reversed the exhaustion of antiviral CD8 1 T cells. 23 Although animals showed clinical signs with the systemic administration of IL-7, there is no direct evidence that endogenous IL-7 regulates antiviral immune responses in the liver.…”

“…Additionally, the inhibition of IL-7 alleviated diabetic diseases. 19,20 Coincidently, clinical investigations reported that exhausted CD8 1 T cells downregulated their cell surface expression of the a chain of the IL-7 receptor (IL-7R; CD127) in chronic hepatitis B virus and hepatitis C virus patients. 14,21,22 Consistent with these observations, Pellegrini and colleagues 23 demonstrated that IL-7 treatment decreased PD-1 expression and reversed T-cell exhaustion in chronic LCMV infection.…”