title: A variable CD3⁺ T-cell frequency in peripheral blood lymphocytes associated with type 1 diabetes mellitus development in the LEW.1AR1-iddm rat.
abstract: OBJECTIVE
  The LEW.1AR1-iddm rat is an animal model of human type 1 diabetes mellitus (T1DM), which arose through a spontaneous mutation within the MHC-congenic inbred strain LEW.1AR1 (RT1(r²)). In contrast to the diabetes-resistant LEW.1AR1 background strain in LEW.1AR1-iddm rats a highly variable T-cell frequency could be observed in peripheral blood lymphocytes (PBLs).
  
  
  METHODS
  In this study we therefore characterised the T-cell repertoire within the PBLs of the two strains by flow cytometry analysis and identified the CD3⁺ T-cell phenotype and its possible linkage to diabetes susceptibility. To map loci conferring susceptibility to variable CD3⁺ T-cell frequency, backcross strains (N2) were generated with the genetically divergent BN and PAR rats for microsatellite analysis.
  
  
  RESULTS
  The LEW.1AR1-iddm rat strain was characterised by a higher variability of CD3⁺ T-cells in PBLs along with a slightly decreased mean value compared to the LEW.1AR1 background strain. The reason for this reduction was a decrease in the CD4⁺ T-cell count while the CD8⁺ T-cell proportion remained unchanged. However, both T-cell subpopulations showed a high variability. This resulted in a lower CD4⁺/CD8⁺ T-cell ratio than in LEW.1AR1 rats. Like LEW.1AR1-iddm rats all animals of the backcross populations, N2 BN and N2 PAR rats, also showed large variations of the CD3⁺ T-cell frequency. The phenotype of variable CD3⁺ T-cell frequency mapped to the telomeric region of chromosome 1 (RNO1), which is identical with the already known Iddm8 diabetes susceptibility region. The data indicate that a variable CD3⁺ T-cell frequency in PBLs is genetically linked to diabetes susceptibility in the LEW.1AR1-iddm rat.
  
  
  CONCLUSIONS
  The T-cell variability in PBLs could be related to the previously reported imbalance between regulatory and effector T-cell populations which results in beta-cell autoimmunity. Since similar T-cell phenotypes have also been described in human T1DM the identification of the functional role of the observed variable CD3⁺ T-cell frequency may help to understand the mechanisms of autoimmunity in T1DM.
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Arndt
authors.forename: Anne
authors.initials: A
authors.lastname: Jörns
authors.forename: Heike
authors.initials: H
authors.lastname: Weiss
authors.forename: Markus
authors.initials: M
authors.lastname: Tiedge
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Hedrich
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lenzen
authors.forename: Dirk
authors.initials: D
authors.lastname: Wedekind
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000276:immunology*; D016516:CD4-CD8 Ratio; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005819:Genetic Markers; D018895:Microsatellite Repeats / Q000235:genetics; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D017252:CD3 Complex; D005819:Genetic Markers