Processing and presentation of (pro)-insulin in the MHC class II pathway: the generation of antigen-based immunomodulators in the context of type 1 diabetes mellitus.
Both CD4(+) and CD8(+) T lymphocytes play a crucial role in the autoimmune process leading to T1D. Dendritic cells take up foreign antigens and autoantigens; within their endocytic compartments, proteases degrade exogenous antigens for subsequent presentation to CD4(+) T cells via MHC class II molecules. A detailed understanding of autoantigen processing and the identification of autoantigenic T cell epitopes are crucial for the development of antigen-based specific immunomodulators. APL are peptide analogues of auto-immunodominant T cell epitopes that bind to MHC class II molecules and can mediate T cell activation. However, APL can be rapidly degraded by proteases occurring in the extracellular space and inside cells, substantially weakening their efficiency. By contrast, protease-resistant APL function as specific immunomodulators and can be used at low doses to examine the functional plasticity of T cells and to potentially interfere with autoimmune responses. Here, we review the latest achievements in (pro)-insulin processing in the MHC class II pathway and the generation of APL to mitigate autoreactive T cells and to activate Treg cells.
Burster
Timo
T
Division of Endocrinology and Diabetes, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany. timo.burster@uniklinik-ulm.de
Boehm
Bernhard O
BO
D000818:Animals; D017951:Antigen Presentation; D002403:Cathepsins / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D003888:Desensitization, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007155:Immunologic Factors / Q000502:physiology; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D010446:Peptide Fragments / Q000276:immunology; D011384:Proinsulin / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000949:Histocompatibility Antigens Class II; D007155:Immunologic Factors; D010446:Peptide Fragments; D011384:Proinsulin; D002403:Cathepsins