Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes

Howard R. Seay, Erik Yusko, Stephanie J. Rothweiler, Lin Zhang, Amanda L. Posgai, Martha Campbell-Thompson, Marissa Vignali, Ryan O. Emerson, John S. Kaddis, Dave Ko, Maki Nakayama, Mia J. Smith, John C. Cambier, Alberto Pugliese, Mark A. Atkinson, Harlan S. Robins, Todd M. Brusko

Research output: Contribution to journalArticle

Abstract

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 β 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.

Original languageEnglish (US)
Pages (from-to)e88242
JournalJCI insight
Volume1
Issue number20
StatePublished - Dec 8 2016

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Tissue Distribution
Type 1 Diabetes Mellitus
B-Lymphocytes
T-Lymphocytes
T-Cell Antigen Receptor
Glutamate Decarboxylase
Clone Cells
Lymph Nodes
Tissue Donors
Proinsulin
Immunoglobulin Heavy Chains
Islets of Langerhans
Blood Cells
Nucleotides
Lymphocytes
Antigens
Amino Acids
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Seay, H. R., Yusko, E., Rothweiler, S. J., Zhang, L., Posgai, A. L., Campbell-Thompson, M., ... Brusko, T. M. (2016). Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes. JCI insight, 1(20), e88242.

Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes. / Seay, Howard R.; Yusko, Erik; Rothweiler, Stephanie J.; Zhang, Lin; Posgai, Amanda L.; Campbell-Thompson, Martha; Vignali, Marissa; Emerson, Ryan O.; Kaddis, John S.; Ko, Dave; Nakayama, Maki; Smith, Mia J.; Cambier, John C.; Pugliese, Alberto; Atkinson, Mark A.; Robins, Harlan S.; Brusko, Todd M.

In: JCI insight, Vol. 1, No. 20, 08.12.2016, p. e88242.

Research output: Contribution to journalArticle

Seay, HR, Yusko, E, Rothweiler, SJ, Zhang, L, Posgai, AL, Campbell-Thompson, M, Vignali, M, Emerson, RO, Kaddis, JS, Ko, D, Nakayama, M, Smith, MJ, Cambier, JC, Pugliese, A, Atkinson, MA, Robins, HS & Brusko, TM 2016, 'Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes', JCI insight, vol. 1, no. 20, pp. e88242.
Seay HR, Yusko E, Rothweiler SJ, Zhang L, Posgai AL, Campbell-Thompson M et al. Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes. JCI insight. 2016 Dec 8;1(20):e88242.
Seay, Howard R. ; Yusko, Erik ; Rothweiler, Stephanie J. ; Zhang, Lin ; Posgai, Amanda L. ; Campbell-Thompson, Martha ; Vignali, Marissa ; Emerson, Ryan O. ; Kaddis, John S. ; Ko, Dave ; Nakayama, Maki ; Smith, Mia J. ; Cambier, John C. ; Pugliese, Alberto ; Atkinson, Mark A. ; Robins, Harlan S. ; Brusko, Todd M. / Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes. In: JCI insight. 2016 ; Vol. 1, No. 20. pp. e88242.
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abstract = "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 β 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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AU - Campbell-Thompson, Martha

AU - Vignali, Marissa

AU - Emerson, Ryan O.

AU - Kaddis, John S.

AU - Ko, Dave

AU - Nakayama, Maki

AU - Smith, Mia J.

AU - Cambier, John C.

AU - Pugliese, Alberto

AU - Atkinson, Mark A.

AU - Robins, Harlan S.

AU - Brusko, Todd M.

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