Autoreactive CD8 T cells associated with beta cell destruction in type 1 diabetes.
Type 1 diabetes is a T cell-mediated autoimmune disease, and insulin is an important target of the autoimmune response associated with beta cell destruction. The mechanism of destruction is still unknown. Here, we provide evidence for CD8 T cell autoreactivity associated with recurrent autoimmunity and loss of beta cell function in type 1 diabetic islet transplant recipients. We first identified an insulin B chain peptide (insB10-18) with extraordinary binding affinity to HLA-A2(*0201) that is expressed by the majority of type 1 diabetes patients. We next demonstrated that this peptide is naturally processed by both constitutive and immuno proteasomes and translocated to the endoplasmic reticulum by the peptide transporter TAP1 to allow binding to HLA-A2 in the endoplasmic reticulum and cell surface presentation. Peripheral blood mononuclear cells from a healthy donor were primed in vitro with this peptide, and CD8 T cells were isolated that specifically recognize target cells expressing the insulin B chain peptide. HLA-A2(insB10-18) tetramer staining revealed a strong association between detection of autoreactive CD8 T cells and recurrent autoimmunity after islet transplantation and graft failure in type 1 diabetic patients. We demonstrate that CD8 T cell autoreactivity is associated with beta cell destruction in type 1 diabetes in humans.
Pinkse
Gabrielle G M
GG
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
Tysma
Odette H M
OH
Bergen
Cees A M
CA
Kester
Michel G D
MG
Ossendorp
Ferry
F
van Veelen
Peter A
PA
Keymeulen
Bart
B
Pipeleers
Danny
D
Drijfhout
Jan W
JW
Roep
Bart O
BO
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D053804:Granzymes; D015234:HLA-A Antigens / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology*; D007371:Interferon-gamma / Q000096:biosynthesis; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012697:Serine Endopeptidases / Q000096:biosynthesis
D001324:Autoantigens; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D007328:Insulin; D010446:Peptide Fragments; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D046988:Proteasome Endopeptidase Complex