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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.

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.

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