Journal
JCI INSIGHT
Volume 1, Issue 20, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.88242
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Funding
- NCATS NIH HHS [UL1 TR001082] Funding Source: Medline
- NIAID NIH HHS [R21 AI124488, P01 AI042288] Funding Source: Medline
- NIDDK NIH HHS [UC4 DK104194, R01 DK096492, R01 DK099317, U01 DK104162, U01 DK104147, R01 DK106191] Funding Source: Medline
- NIH HHS [F30 OD021477, T32 OD012201] Funding Source: Medline
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The adaptive immune repertoire plays a critical role in type 1 diabetes (T1D) pathogenesis. However, efforts to characterize B cell and T cell receptor (TCR) profiles in T1D subjects have been largely limited to peripheral blood sampling and restricted to known antigens. To address this, we collected pancreatic draining lymph nodes (pLN), irrelevant nonpancreatic draining lymph nodes, peripheral blood mononuclear cells (PBMC), and splenocytes from T1D subjects (n = 18) and control donors (n = 9) as well as pancreatic islets from 1 T1D patient; from these tissues, we collected purified CD4(+) conventional T cells (Tconv), CD4(+) Treg, CD8(+) T cells, and B cells. By conducting high-throughput immunosequencing of the TCR beta chain (TRB) and B cell receptor (BCR) immunoglobulin heavy chain (IGH) on these samples, we sought to analyze the molecular signature of the lymphocyte populations within these tissues and of T1D. Ultimately, we observed a highly tissue-restricted CD4(+) repertoire, while up to 24% of CD8(+) clones were shared among tissues. We surveyed our data set for previously described proinsulin-and glutamic acid decarboxylase 65-reactive (GAD65-reactive) receptors, and interestingly, we observed a TRB with homology to a known GAD65-reactive TCR (clone GAD4.13) present in 7 T1D donors (38.9%), representing >25% of all productive TRB within Tconv isolated from the pLN of 1 T1D subject. These data demonstrate diverse receptor signatures at the nucleotide level and enriched autoreactive clones at the amino acid level, supporting the utility of coupling immunosequencing data with knowledge of characterized autoreactive receptors.
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