TY - UNPB
T1 - Identification of a type 1 diabetes-associated T cell receptor repertoire signature from the human peripheral blood
AU - Rawat, Puneet
AU - Shapiro, Melanie R.
AU - Peters, Leeana D.
AU - Widrich, Michael
AU - Mayer-Blackwell, Koshlan
AU - Motwani, Keshav
AU - Pavlović, Milena
AU - al Hajj, Ghadi
AU - Posgai, Amanda L.
AU - Kanduri, Chakravarthi
AU - Isacchini, Giulio
AU - Chernigovskaya, Maria
AU - Scheffer, Lonneke
AU - Motwani, Kartik
AU - Balzano-Nogueira, Leandro Octavio
AU - Pettenger-Willey, Camryn M.
AU - Valkiers, Sebastiaan
AU - Jacobsen, Laura
AU - Haller, Michael J.
AU - Schatz, Desmond A.
AU - Wasserfall, Clive H.
AU - Emerson, Ryan O.
AU - Fiore-Gartland, Andew J.
AU - Atkinson, Mark A.
AU - Klambauer, Günter
AU - Sandve, Geir K.
AU - Greiff, Viktor
AU - Brusko, Todd M.
PY - 2024/12/12
Y1 - 2024/12/12
N2 - Type 1 Diabetes (T1D) is a T-cell mediated disease with a strong immunogenetic HLA dependence. HLA allelic influence on the T cell receptor (TCR) repertoire shapes thymic selection and controls activation of diabetogenic clones, yet remains largely unresolved in T1D. We sequenced the circulating TCRβ chain repertoire from 2250 HLA-typed individuals across three cross-sectional cohorts, including T1D patients, and healthy related and unrelated controls. We found that HLA risk alleles show higher restriction of TCR repertoires in T1D individuals. Machine learning analysis yielded AUROC of 0.77 on test cohorts for T1D classification. T1D-specific TCR features predominantly localized to the subsequence motifs, indicating absence of T1D-associated public clones. These TCR motifs were also observed in independent TCR cohorts residing in pancreas-draining lymph nodes of T1D individuals. Collectively, our data demonstrate T1D-related TCR motif enrichment based on genetic risk, offering a potential metric for autoreactivity and basis for TCR-based diagnostics and therapeutics.
AB - Type 1 Diabetes (T1D) is a T-cell mediated disease with a strong immunogenetic HLA dependence. HLA allelic influence on the T cell receptor (TCR) repertoire shapes thymic selection and controls activation of diabetogenic clones, yet remains largely unresolved in T1D. We sequenced the circulating TCRβ chain repertoire from 2250 HLA-typed individuals across three cross-sectional cohorts, including T1D patients, and healthy related and unrelated controls. We found that HLA risk alleles show higher restriction of TCR repertoires in T1D individuals. Machine learning analysis yielded AUROC of 0.77 on test cohorts for T1D classification. T1D-specific TCR features predominantly localized to the subsequence motifs, indicating absence of T1D-associated public clones. These TCR motifs were also observed in independent TCR cohorts residing in pancreas-draining lymph nodes of T1D individuals. Collectively, our data demonstrate T1D-related TCR motif enrichment based on genetic risk, offering a potential metric for autoreactivity and basis for TCR-based diagnostics and therapeutics.
KW - genetic and genomic medicine
UR - https://www.medrxiv.org/content/10.1101/2024.12.10.24318751v1
U2 - 10.1101/2024.12.10.24318751
DO - 10.1101/2024.12.10.24318751
M3 - Preprint
BT - Identification of a type 1 diabetes-associated T cell receptor repertoire signature from the human peripheral blood
ER -
