Microbial antigen mimics activate diabetogenic CD8 T cells in NOD mice.
Both animal model and human studies indicate that commensal bacteria may modify type 1 diabetes (T1D) development. However, the underlying mechanisms by which gut microbes could trigger or protect from diabetes are not fully understood, especially the interaction of commensal bacteria with pathogenic CD8 T cells. In this study, using islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive CD8 T cell receptor NY8.3 transgenic nonobese diabetic mice, we demonstrated that MyD88 strongly modulates CD8(+) T cell-mediated T1D development via the gut microbiota. Some microbial protein peptides share significant homology with IGRP. Both the microbial peptide mimic of Fusobacteria and the bacteria directly activate IGRP-specific NY8.3 T cells and promote diabetes development. Thus, we provide evidence of molecular mimicry between microbial antigens and an islet autoantigen and a novel mechanism by which the diabetogenicity of CD8(+) T cells can be regulated by innate immunity and the gut microbiota.
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
Ningwen
N
Tai
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
Jian
J
Peng
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520 Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
Fuqiang
F
Liu
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
Elke
0000-0002-8352-7240
E
Gulden
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
Youjia
Y
Hu
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
Xiaojun
X
Zhang
Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
Li
L
Chen
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, UK.
F Susan
0000-0002-2812-8845
FS
Wong
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520 li.wen@yale.edu.
Li
0000-0002-8805-2934
L
Wen
D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D005260:Female; D000069196:Gastrointestinal Microbiome; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013950:Thymus Gland / Q000473:pathology
D000942:Antigens, Bacterial; D053594:Myeloid Differentiation Factor 88; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse