A peptide of glutamic acid decarboxylase 65 can recruit and expand a diabetogenic T cell clone, BDC2.5, in the pancreas.
Self peptide-MHC ligands create and maintain the mature T cell repertoire by positive selection in the thymus and by homeostatic proliferation in the periphery. A low affinity/avidity interaction among T cells, self peptides, and MHC molecules has been suggested for these events, but it remains unknown whether or how this self-interaction is involved in tolerance and/or autoimmunity. Several lines of evidence implicate the glutamic acid decarboxylase 65 (GAD-65) peptide, p524-543, as a specific, possibly low affinity, stimulus for the spontaneously arising, diabetogenic T cell clone BDC2.5. Interestingly, BDC2.5 T cells, which normally are unresponsive to p524-543 stimulation, react to the peptide when provided with splenic APC obtained from mice immunized with the same peptide, p524-543, but not, for example, with hen egg white lysozyme. Immunization with p524-543 increases the susceptibility of the NOD mice to type 1 diabetes induced by the adoptive transfer of BDC2.5 T cells. In addition, very few CFSE-labeled BDC2.5 T cells divide in the recipient's pancreas after transfer into a transgenic mouse that overexpresses GAD-65 in B cells, whereas they divide vigorously in the pancreas of normal NOD recipients. A special relationship between the BDC2.5 clone and the GAD-65 molecule is further demonstrated by generation of a double-transgenic mouse line carrying both the BDC2.5 TCR and GAD-65 transgenes, in which a significant reduction of BDC2.5 cells in the pancreas has been observed, presumably due to tolerance induction. These data suggest that unique and/or altered processing of self Ags may play an essential role in the development and expansion of autoreactive T cells.
Dai
Yang D
YD
Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
Jensen
Kent P
KP
Lehuen
Agnes
A
Masteller
Emma L
EL
Bluestone
Jeffrey A
JA
Wilson
Darcy B
DB
Sercarz
Eli E
EE
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity; D049109:Cell Proliferation; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D002999:Clone Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000276:immunology*; D007108:Immune Tolerance; D051379:Mice; D016688:Mice, Inbred NOD / Q000276:immunology*; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D010446:Peptide Fragments; D005968:Glutamate Decarboxylase; C505593:glutamic acid decarboxylase 65 (524-543), mouse