GAD65-specific CD4+ T-cells with high antigen avidity are prevalent in peripheral blood of patients with type 1 diabetes.
Negative selection of self-reactive T-cells during thymic development, along with activation-induced cell death in peripheral lymphocytes, is designed to limit the expansion and persistence of autoreactive T-cells. Autoreactive T-cells are nevertheless present, both in patients with type 1 diabetes and in at-risk subjects. By using MHC class II tetramers to probe the T-cell receptor (TcR) specificity and avidity of GAD65 reactive T-cell clones isolated from patients with type 1 diabetes, we identified high-avidity CD4+ T-cells in peripheral blood, coexisting with low-avidity cells directed to the same GAD65 epitope specificity. A variety of cytokine patterns was observed, even among T-cells with high MHC-peptide avidity, and the clones utilize a biased set of TcR genes that favor two combinations, Valpha12-beta5.1 and Valpha17-Vbeta4. Presence of these high-avidity TcRs indicates a failure to delete autoreactive T-cells that likely arise from oligoclonal expansion in response to autoantigen exposure during the progression of type 1 diabetes.
Reijonen
Helena
H
Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101, USA. reijonen@benaroyaresearch.org
Mallone
Roberto
R
Heninger
Anne-Kristin
AK
Laughlin
Elsa M
EM
Kochik
Sharon A
SA
Falk
Ben
B
Kwok
William W
WW
Greenbaum
Carla
C
Nepom
Gerald T
GT
D000915:Antibody Affinity / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D001782:Blood Donors; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000097:blood*; D006684:HLA-DR Antigens / Q000097:blood; D006801:Humans; D007527:Isoenzymes / Q000097:blood*; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D011948:Receptors, Antigen, T-Cell / Q000097:blood; D012016:Reference Values
D001323:Autoantibodies; D006684:HLA-DR Antigens; D007527:Isoenzymes; D011948:Receptors, Antigen, T-Cell; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2