ABSTRACT
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.
Subject(s)
Diabetes Mellitus, Type 1/immunology , Immunologic Memory , Interleukin-7/immunology , Receptors, Interleukin-7/antagonists & inhibitors , Signal Transduction/immunology , T-Lymphocytes/immunology , Adoptive Transfer , Animals , Antigens, Differentiation/immunology , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 1/therapy , Female , Immune Tolerance , Interferon-gamma/immunology , Lymphocyte Activation , Mice , Mice, Inbred NOD , Programmed Cell Death 1 Receptor , Receptors, Interleukin-7/immunology , T-Lymphocytes/pathologyABSTRACT
IL-2 controls the survival of regulatory T cells (Tregs), but it is unclear whether IL-2 also directly affects Treg suppressive capacity in vivo. We have found that eliminating Bim-dependent apoptosis in IL-2- and CD25-deficient mice restored Treg numbers but failed to cure their lethal autoimmune disease, demonstrating that IL-2-dependent survival and suppressive activity can be uncoupled in Tregs. Treatment with IL-2-anti-IL-2-Ab complexes enhanced the numbers and suppressive capacity of IL-2-deprived Tregs with striking increases in CD25, CTLA-4, and CD39/CD73 expression. Although cytokine treatment induced these suppressive mechanisms in both IL-2(-/-) and IL-2(-/-)Bim(-/-) mice, it only reversed autoimmune disease in the latter. Our results suggest that successful IL-2 therapy of established autoimmune diseases will require a threshold quantity of Tregs present at the start of treatment and show that the suppressive capacity of Tregs critically depends on IL-2 even when Treg survival is independent of this cytokine.
Subject(s)
Interleukin-2/physiology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Anemia, Hemolytic, Autoimmune/genetics , Anemia, Hemolytic, Autoimmune/immunology , Anemia, Hemolytic, Autoimmune/therapy , Animals , Apoptosis Regulatory Proteins/deficiency , Apoptosis Regulatory Proteins/genetics , Bcl-2-Like Protein 11 , Cell Proliferation , Cells, Cultured , Coculture Techniques , Forkhead Transcription Factors/deficiency , Forkhead Transcription Factors/genetics , Gene Deletion , Interleukin-2/genetics , Interleukin-2 Receptor alpha Subunit/deficiency , Interleukin-2 Receptor alpha Subunit/genetics , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, Transgenic , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins/genetics , T-Lymphocytes, Regulatory/pathologyABSTRACT
TEL-AML1 (ETV6-RUNX1) is the most common translocation in the childhood leukemias, and is a prenatal mutation in most children. This translocation has been detected at a high rate among newborns ( approximately 1%); therefore, the rate-limiting event for leukemia seems to be secondary mutations. One such frequent mutation in this subtype is partial deletion of chromosome 12p, trans from the translocation. Nine del(12p) breakpoints within six leukemia cases were sequenced to explore the etiology of this genetic event, and most involved cryptic sterile translocations. Twelve of 18 del(12p) parent sequences involved in these breakpoints were located in repeat regions (8 of these in long interspersed nuclear elements). This stands in contrast with TEL-AML1, in which only 21 of 110 previously assessed breakpoints (19%) occur in DNA repeats (P=0.0001). An exploratory assessment of archived neonatal blood cards revealed significantly more long interspersed nuclear element CpG methylations in individuals at birth who were later diagnosed with TEL-AML1 leukemia, compared with individuals who did not contract leukemia (P=0.01). Nontemplate nucleotides were also more frequent in del(12p) than in TEL-AML1 junctions (P=0.004), suggesting formation by terminal deoxynucleotidyl transferase. Assessment of six archived neonatal blood cards indicated that no del(12p) rearrangements backtracked to birth, although two of these patients were previously positive for TEL-AML1 using the same assay with comparable sensitivity. These data are compatible with a two-stage natural history: TEL-AML1 occurs prenatally, and del(12p) occurs postnatally in more mature cells with a structure that suggests the involvement of retrotransposon instability.