[Frontiers in Bioscience 14, 344-351, January 1, 2009]

Antigen processing patterns determine GAD65-specific regulation vs. pathogenesis

Yang D. Dai, Eli E. Sercarz

Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, La Jolla, California 92121, USA


1. Abstract
2. Introduction
3. Regulation dominates immune response to GAD65 as learned from GAD65 knockout and transgenic studies
4. Exogenous immunization induces regulatory T cells, but endogenous priming generates pathogenic effectors
5. Clustered T cell determinants could include both regulatory and pathogenic epitopes
6. Unique processing of a clustered determinant of GAD65 is required to activate highly diabetogenic T cell clones such as BDC2.5
7. Conclusion
8. Acknowledgment
9. References


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.