T cell receptor (TCR) sequences are a
critical component of tri-molecular complex determining tissue specificity of autoimmune diseases. Recent improvement of
sequencing technology now allows us to expand our understanding of T cell
immunity contributing to the development of type 1 diabetes (T1D). In this presentation, we will discuss several
applications that can be achieved by TCR sequencing. First, TCR sequences are an inherent signature
for individual T cells, and thus are able to be used to trace how T cells infiltrate
and expand between and within organs. Identical
TCR sequences are detected in different portions of pancreas as well as in peripheral
immune organs including the spleen and pancreatic lymph nodes of same
individuals. This finding leads us to
the second application that TCR sequences may be able to be used as biomarker
if those associated with disease status are present and are quantitatively
detectable in peripheral blood. While
individual patients have extremely different TCR repertoires in the pancreas, TCR
sequences shared between individuals, called “public” sequences, still
exist. Sequencing of TCRs having a
particular Vgene (TRAV13-1), which is considered to be preferentially used by
TCRs targeting an insulin peptide presented by a DQ8 molecule, successfully
identified “public” sequences detected only in the peripheral blood of newly-onset
T1D patients but not in non-diabetic siblings nor in long-term T1D patients. Thirdly, identification of TCRs enables us to
discover targeted antigens. TCR alpha
and beta chain sequence pairs responding to an insulin A chain peptide have
been found from the pancreas of a patient having T1D. Lastly, TCR Vgene but not Jgene sequences
encoded in germline may be a critical determinant of antigen specificity
and possibly of disease susceptibility for individuals having specific HLA alleles. Thus, TCR Vgenes may be a potential target for immunotherapy to cure and
prevent T1D.