Skip to main content
eScholarship
Open Access Publications from the University of California

IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells

  • Author(s): Penaranda, C
  • Kuswanto, W
  • Hofmann, J
  • Kenefeck, R
  • Narendran, P
  • Walker, LSK
  • Bluestone, JA
  • Abbas, AK
  • Dooms, H
  • et al.
Abstract

To protect the organism against autoimmunity, self-reactive effector/memory T cells (TE/M) are controlled by cell-intrinsic and -extrinsic regulatory mechanisms. However, how some TE/M cells escape regulation and cause autoimmune disease is currently not understood. Here we show that blocking IL-7 receptor-α (IL-7Rα) with monoclonal antibodies in nonobese diabetic (NOD) mice prevented autoimmune diabetes and, importantly, reversed disease in new-onset diabetic mice. Surprisingly, IL-7-deprived diabetogenic TE/M cells remained present in the treated animals but showed increased expression of the inhibitory receptor Programmed Death 1 (PD-1) and reduced IFN-γ production. Conversely, IL-7 suppressed PD-1 expression on activated T cells in vitro. Adoptive transfer experiments revealed that TE/M cells from anti-IL-7Rα-treated mice had lost their pathogenic potential, indicating that absence of IL-7 signals induces cell-intrinsic tolerance. In addition to this mechanism, IL-7Rα blockade altered the balance of regulatory T cells and TE/M cells, hence promoting cell-extrinsic regulation and further increasing the threshold for diabetogenic T-cell activation. Our data demonstrate that IL-7 contributes to the pathogenesis of autoimmune diabetes by enabling TE/M cells to remain in a functionally competent state and suggest IL-7Rα blockade as a therapy for established T-cell-dependent autoimmune diseases.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Main Content
Current View