title: HLA-DR*0401 expression in the NOD mice prevents the development of autoimmune diabetes by multiple alterations in the T-cell compartment.
abstract: Several human HLA alleles have been found associated with type 1 diabetes (T1D), but their precise role is not clearly defined. Herein, we report that a human MHC class II (HLA-DR*0401) allele transgene that has been expressed into NOD (H-2(g7)I-E(null)) mice prone to T1D rendered the mice resistant to the disease. T1D resistance occurred in the context of multi-point T-cell alterations such as: (i) skewed CD4/CD8 T-cell ratio, (ii) decreased size of CD4(+)CD44(high) T memory pool, (iii) aberrant TCR Vβ repertoire, (iv) increased neonatal number of Foxp3(+) and TR-1(+) regulatory cells, and (v) reduced IFN-γ inflammatory response vs. enhanced IL-10 suppressogenic response of T-cells upon polyclonal and antigen-specific stimulation. The T-cells from NOD/DR4 Tg mice were unable to induce or suppress diabetes in NOD/RAG deficient mice. This study describes a multifaceted regulatory function of the HLA-DR*0401 allele strongly associated with the lack of T1D development in NOD mice.
authors.affiliation: Uniformed Services University of the Health Sciences, Department of Medicine, Division of Immunology, Bethesda, MD 20814, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Pow Sang
authors.affiliation: Uniformed Services University of the Health Sciences, Department of Medicine, Division of Immunology, Bethesda, MD 20814, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Surls
authors.affiliation: Uniformed Services University of the Health Sciences, Department of Medicine, Division of Immunology, Bethesda, MD 20814, USA.
authors.forename: Mirian
authors.initials: M
authors.lastname: Mendoza
authors.affiliation: Uniformed Services University of the Health Sciences, Department of Medicine, Division of Immunology, Bethesda, MD 20814, USA; Naval Medical Research Center, Walter Reed Army Institute of Research, Infectious Diseases Directorate-Malaria Program, Silver Spring, MD 20910, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Casares
authors.affiliation: Uniformed Services University of the Health Sciences, Department of Medicine, Division of Immunology, Bethesda, MD 20814, USA. Electronic address: teodor-doru.brumeanu@usuhs.edu.
authors.forename: Teodor
authors.initials: T
authors.lastname: Brumeanu
mesh_terms: D000818:Animals; D016516:CD4-CD8 Ratio; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control*; D006684:HLA-DR Antigens / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D006684:HLA-DR Antigens; C556062:IL10 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: HLA-DR*0401; NOD humanized mice; T-cell regulation; Type 1 diabetes