title: Broad induction of immunoregulatory mechanisms after a short course of anti-IL-7Rα antibodies in NOD mice.
abstract: Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of the insulin-producing β-cells in the pancreas. Therefore, approaches that effectively halt the pathogenic T cell response are predicted to have preventive or therapeutic benefit for type 1 diabetes patients. We previously demonstrated that long-term blocking of IL-7 signaling, which is critical for the survival and function of T cells, prevented and reversed type 1 diabetes in non-obese diabetic mice. However, such persistent inhibition of T cell responses raises concerns about causing immunodeficiency. Here, we asked whether a reduced duration of the treatment with anti-IL-7Rα antibodies retained efficacy in preventing diabetes. Moreover, we sought to identify immunoregulatory mechanisms induced by anti-IL-7Rα administration.
  
  
  
  Anti-IL-7Rα antibodies were administered to prediabetic NOD mice for 3 weeks and blood samples were taken at the end of treatment and 2 weeks later to analyze changes in T cell phenotypes in response to IL-7Rα blockade. We found that the co-inhibitory receptors LAG-3, Tim-3 and PD-1 were increased on peripheral blood CD4+and CD8+T cells from anti-IL-7Rα-treated mice. Expression of these receptors contributed to reduced T cell cytokine production in response to TCR stimulation. In addition, the frequency of Tregs within the circulating CD4+T cells was increased at the end of anti-IL-7Rα antibody treatment and these Tregs showed a more activated phenotype. In vitro restimulation assays revealed that effector T cells from anti-IL-7Rα-treated mice were more sensitive to co-inhibitory receptor induction after TCR stimulation. Importantly, these changes were accompanied by delayed type 1 diabetes disease kinetics.
  
  
  
  Together, our data show that short-term blockade of IL-7Rα induces detectable changes in co-inhibitory receptor expression and Treg frequencies in peripheral blood of NOD mice. These changes appear to have long-lasting effects by delaying or preventing type 1 diabetes incidence. Hence, our study provides further support for using anti-IL-7Rα antibodies to modulate autoreactive T cell responses.
authors.affiliation: Department of Medicine, Arthritis Center/Rheumatology Section, Boston University School of Medicine, 72 East Concord Street, E519, Boston, MA, 02118, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Vazquez-Mateo
authors.affiliation: Department of Medicine, Arthritis Center/Rheumatology Section, Boston University School of Medicine, 72 East Concord Street, E519, Boston, MA, 02118, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Collins
authors.affiliation: Department of Medicine, Arthritis Center/Rheumatology Section, Boston University School of Medicine, 72 East Concord Street, E519, Boston, MA, 02118, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Fleury
authors.affiliation: Department of Medicine, Arthritis Center/Rheumatology Section, Boston University School of Medicine, 72 East Concord Street, E519, Boston, MA, 02118, USA. hdooms@bu.edu.
authors.forename: Hans
authors.identifier: 0000-0001-7964-0876
authors.initials: H
authors.lastname: Dooms
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015851:Interleukin-7 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D015851:Interleukin-7; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D020395:Receptors, Interleukin-7; D000093322:Lymphocyte Activation Gene 3 Protein
keywords: Autoimmunity; Inhibitory receptors; Interleukin 7; Non-obese diabetic mice; T cells; Tregs; Type 1 diabetes