Antigen processing patterns determine GAD65-specific regulation vs. pathogenesis.
Alterations in presenting self determinants to T cells may depend upon the availability of sites on the molecule adjacent to known determinants to different processing enzymes, or, at the level of amino acid sequence or conformation of a single determinant. We have studied three possible ways that could modulate the processing and presentation of T cell determinants of a diabetes autoantigen, glutamic acid decarboxylase (GAD) 65, which could contribute to induction of GAD65-specific regulatory versus pathogenic T cells in type 1 diabetes (T1D): 1) enhanced presentation of subdominant/cryptic determinants to T cells that have not been well-tolerized, which may activate T cells of high affinity and high aggressiveness; 2) trimming or truncating flanking residues which may otherwise provide needed binding energy to determinants that activate regulatory cells, thus releasing autoaggressive T cells from suppression; 3) biochemical or chemical modifications of self antigens in an inflammatory environment or within activated antigen presenting cells (APC) which may convert a previously regulatory antigen or determinant into a disease-causing one that activates autoreactive T cells at a higher affinity.
Dai
Yang D
YD
Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, La Jolla, California 92121, USA. ydai@tpims.org
Sercarz
Eli E
EE
D000818:Animals; D030801:Animals, Genetically Modified; D055786:Gene Knockout Techniques; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2