Germline-like TCR alpha chains shared between autoreactive T cells in blood and pancreas [dataset1]
How human islet antigen reactive CD4+ memory T cells (IAR T cells) from peripheral blood affect Type 1 Diabetes (T1D) progression in the pancreas is poorly understood. We identified paired alpha/beta (TRA/TRB) T cell receptors (TCRs) in IAR T cells from the blood of healthy, at-risk, new onset, and established T1D donors, and measured sequence overlap with TCRs in pancreata from organ donors. We detected extensive TRA junction sharing between IAR T cells and pancreatic infiltrating T cells (PIT), with perfect or single mismatched TRA junction amino acid sequences comprising ~34% of unique IAR TRA junctions. PIT-matched TRA junctions were largely public, and showed significant nucleotide sequence convergence, increased use of germline-encoded residues in epitope engagement, and a potential for cross-reactivity. The link with T cells in the pancreas implicates autoreactive IAR T cells with shared TRA junctions in the prediabetic and new onset phases of T1D progression. Overall design: Islet antigen reactive CD4 T cells were isolated using a CD154 activation assay from cryopreserved PBMC of a cross-sectional cohort of islet autoantibody (Aab) negative (n=6), 1 Aab+ >18y (n=6), 1 Aab+ <14y (n=3), and >1 Aab+ (n=6) donors with increasing risk for progression to T1D. Activated IAR T cells were single-cell sorted and analyzed by single-cell RNA-sequencing to identify T cell receptor a/ß pairs in parallel with full transcript profiles.