IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells.
To protect the organism against autoimmunity, self-reactive effector/memory T cells (T(E/M)) are controlled by cell-intrinsic and -extrinsic regulatory mechanisms. However, how some T(E/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 T(E/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 T(E/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 T(E/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 T(E/M) cells to remain in a functionally competent state and suggest IL-7Rα blockade as a therapy for established T-cell-dependent autoimmune diseases.
Diabetes Center, University of California, San Francisco, CA 94143, USA.
Cristina
C
Penaranda
Wilson
W
Kuswanto
Jerry
J
Hofmann
Rupert
R
Kenefeck
Parth
P
Narendran
Lucy S K
LS
Walker
Jeffrey A
JA
Bluestone
Abul K
AK
Abbas
Hans
H
Dooms
D019264:Adoptive Transfer; D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D005260:Female; D007108:Immune Tolerance; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D061026:Programmed Cell Death 1 Receptor; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D000943:Antigens, Differentiation; D015851:Interleukin-7; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D007371:Interferon-gamma