beta cell-specific CD4+ T cell clonotypes in peripheral blood and the pancreatic islets are distinct.
Type 1 diabetes is an autoimmune disease mediated by beta cell-specific CD4(+) and CD8(+) T cells. Tracking beta cell-specific T cells is one approach to monitor the diabetogenic response in at risk or diabetic individuals. Such analyses, however, are limited to PBL because T cells infiltrating the pancreatic islets are normally inaccessible. A key issue is whether peripheral beta cell-specific T cells accurately reflect those cells infiltrating the target tissue. We investigated the properties of CD4(+) T cells specific for a mimetic epitope recognized by the BDC2.5 clonotypic TCR in NOD mice. Soluble IA(g7)-Ig (sIA(g7)-Ig) multimer complexes covalently linked to a mimetic BDC peptide (sIA(g7)-mBDC) were used to identify or isolate CD4(+) T cells from PBL and the islets of NOD mice. A temporal increase in sIA(g7)-mBDC binding (g7-mBDC(+)) T cells corresponding with the progression of beta cell autoimmunity was detected in both PBL and islets in NOD female mice. In contrast to T cells in PBL, however, the majority of islet g7-mBDC(+) T cells exhibited a type 1 phenotype, and mediated diabetes upon transfer into NOD.scid recipients. TCR-beta and CDR-beta gene usage of single islet-infiltrating g7-mBDC(+) CD4(+) T cells from individual NOD mice showed a restricted repertoire dominated by one or two clones typically expressing TCR beta-chain variable TRBV-15. In contrast, a distinct and diverse TCR repertoire was detected for PBL-derived g7-mBDC(+) T cells. These results demonstrate that PBL and islet CD4(+) T cells specific for a given beta cell epitope can differ regarding pathogenicity and TCR repertoire.
Li
Li
L
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
He
Qiuming
Q
Garland
Alaina
A
Yi
Zuoan
Z
Aybar
Lydia T
LT
Kepler
Thomas B
TB
Frelinger
Jeffrey A
JA
Wang
Bo
B
Tisch
Roland
R
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002999:Clone Cells; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D050417:Insulin-Secreting Cells / Q000276:immunology*; D007515:Islets of Langerhans / Q000166:cytology* / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology