Abstract
The T cell antigens driving autoimmune Type 1 Diabetes (T1D) have been pursued for more than three decades. When diabetogenic CD4 T cell clones and their relevant MHCII antigen presenting alleles were first identified in rodents and humans, the path to discovering the peptide epitopes within pancreatic beta cell proteins seemed straightforward. However, as experimental results accumulated, definitive data were often absent or controversial. Work within the last decade has helped to clear up some of the controversy by demonstrating that a number of the important MHCII presented epitopes are not encoded in the natural beta cell proteins, but in fact are fusions between peptide fragments derived from the same or different proteins. Recently, the mechanism for generating these MHCII diabetogenic chimeric epitopes has been attributed to a form of reverse proteolysis, called transpeptidation, a process that has been well-documented in the production of MHCI presented epitopes. In this mini-review we summarize these data and their implications for T1D and other autoimmune responses.
Highlights
In the Non-Obese Diabetic (NOD) mouse model of Type 1 Diabetes (T1D), a variety of CD4 T cell clones or T cell hybridomas were prepared that responded to antigens within the secretory granules of the beta cells of pancreatic islets of Langerhans [1, 2]
We noticed that there was a conserved 14 amino peptide (WE14) [26] released from chromogranin A (ChgA) during prohormone convertase processing leaving the WSRMD sequence at its C-terminus, while removing the inhibitory amino acids. This peptide stimulated Barbara Davis Center (BDC)-2.5 and BDC-10.1 weakly, presumably because of the missing p1 to p4 amino acids, but we found that pancreatic islets from mice lacking a functional ChgA gene failed to stimulate these T cell leading us to the conclusion that, while the WE14 peptide was in some way involved in the ChgA derived epitope, a post-translational modification was likely required to make up for the loss at the p1 to p4 positions in the epitope [25]
For ChgA, based on the highly stimulatory activity of the RLGL when added to the N-terminus of WE14 [19, 29], we looked in well expressed beta cell granule proteins for similar sequences that could be added to WE14 to make similar complete epitopes predicted to stimulate the BDC10.1 and/or BCD-2.5 T cell [29]
Summary
In the Non-Obese Diabetic (NOD) mouse model of T1D, a variety of CD4 T cell clones or T cell hybridomas were prepared that responded to antigens within the secretory granules of the beta cells of pancreatic islets of Langerhans [1, 2]. A number of T cell clones failed this test, but others, originally isolated by investigators at the Barbara Davis Center (BDC) [1, 2] were very active. It has taken an effort of more than two decades to identify the functional peptide epitopes recognized by these BDC CD4 T cells. This work has identified diabetogenic CD4 T cell epitopes derived in part from three beta cell proteins - insulin, chromogranin A (ChgA) and islet amyloid polypeptide (IAPP). We begin with a short review of how these three altered antigenic epitopes were discovered
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
