Analysis of T cell receptor and specificity of T cells in the islets of type 1 diabetes organ donors

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Abstract Summary

Background: T-cell receptors (TCRs) used by T cells in the islets and antigens targeted by such T-cells may be utilized for T-cell biomarkers and therapeutic purposes for type 1 diabetes (T1D). Thus, we aimed to determine islet-specific TCR repertoires and their antigen specificity.

Methods: We isolated 1,478 CD4 and 1,123 CD8 T-cells from islets of six organ donors having T1D, and identified TCR alpha and beta chain sequences of each single cell using Illumina-MiSEQ. To seek antigen specificity, TCR transductants were analyzed for the response to candidate antigens.

Results: We identified 1,637 alpha and 1,967 beta in-frame TCR sequences. A large number of T-cells in each donor (26%-71%) had identical clonotypes, suggesting that these cells expanded upon antigen stimulation. Furthermore, 6 TCRs were detected in the islets of multiple donors. Notably, donors having the identical clonotypes shared at least one HLA class-I or II alleles when the clonotypes were found from CD8 or CD4 T-cells, respectively. Next, we analyzed antigen specificity for frequently detected TCRs. Preproinsulin 2-14 and 15-24 presented by HLA-A2 were recognized by TCRs that were found from CD8 T-cells in the islets of multiple donors. Regarding TCRs derived from CD4 T-cells, we detected reactivity to insulin B-chain 9-23 presented by DQ8 and DP4, and C:peptide 19-35 presented by DQ8-trans. Remarkably, further analysis determined that ZnT8 270-279 presented by DP4 is an epitope for one of the “public” TCRs detected in the islets of multiple T1D donors.

Conclusions: “Public” TCR clonotypes that may be utilizable for surrogate T1D T-cell biomarkers exist. We confirmed common reactivity to epitopes within preproinsulin and ZnT8 by CD4 and CD8 T-cells in the islets. Particularly, specificity to epitopes presented by HLA-DP4, which is expressed by approximately half of humans in the world and therefore can be beneficial for a large number of patients, suggests utilizing DP4-specific antigens as diagnostic and therapeutic tools for T1D. 

Submission ID :
IDS60242
Submission Type
Abstract Topics
Barbara Davis Center, University of Colorado Denver
Barbara Davis Center, University of Colorado Denver
Barbara Davis Center, University of Colorado Denver
University of Colorado Denver
University of Massachusetts Medical School
University of Florida
Vanderbilt University
City of Hope
Barbara Davis Center, University of Colorado Denver

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IDS75126
Poster Session A
Poster and oral
Dr Michelle So
8 visits

KEY DATES

Event dates:
Thursday 25 October - Monday 29 October 2018

Abstract submission deadline:
Monday 14 May 2018

Abstract notification:
July 2018

Early registration deadline:
Monday 3 September 2018

Registration deadline:
Monday 15 October 2018

Contact
British Society for Immunology
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