Increased effector memory insulin-specific CD4+ T cells correlate with insulin autoantibodies in patients with recent-onset type 1 diabetes

Justin A Spanier, Nathanael L. Sahli, Joseph C. Wilson, Tijana Martinov, Dileepan T, Adam L. Burrack, Erik B Finger, Bruce R Blazar, Aaron W. Michels, Antoinette Moran, Marc Jenkins, Brian T Fife

Research output: Contribution to journalArticle

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Abstract

Type 1 diabetes (T1D) results from T cell-mediated destruction of insulin-producing β-cells. Insulin represents a key self-antigen in disease pathogenesis, as recent studies identified proinsulin-responding T cells from inflamed pancreatic islets of organ donors with recent-onset T1D. These cells respond to an insulin B-chain (InsB) epitope presented by the HLA-DQ8 molecule associated with high T1D risk. Understanding insulin-specific T-cell frequency and phenotype in peripheral blood is now critical. We constructed fluorescent InsB10-23:DQ8 tetramers, stained peripheral blood lymphocytes directly ex vivo, and show DQ8+ patients with T1D have increased tetramer+ CD4+ T cells compared with HLA-matched control subjects without diabetes. Patients with a shorter disease duration had higher frequencies of insulin-reactive CD4+ T cells, with most of these cells being antigen experienced. We also demonstrate that the number of insulin tetramer+ effector memory cells is directly correlated with insulin antibody titers, suggesting insulin-specific T- and B-cell interactions. Notably, one of four control subjects with tetramer+ cells was a first-degree relative who had insulin-specific cells with an effector memory phenotype, potentially representing an early marker of T-cell autoimmunity. Our results suggest that studying InsB10-23:DQ8 reactive T-cell frequency and phenotype may provide a biomarker of disease activity in patients with T1D and those at risk.

Original languageEnglish (US)
Pages (from-to)3051-3060
Number of pages10
JournalDiabetes
Volume66
Issue number12
DOIs
StatePublished - Dec 1 2017

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Type 1 Diabetes Mellitus
Autoantibodies
Insulin
T-Lymphocytes
Phenotype
Insulin Antibodies
Proinsulin
Autoantigens
Autoimmunity
Islets of Langerhans
Cell Communication
Epitopes
B-Lymphocytes
Biomarkers
Tissue Donors
Lymphocytes
Antigens

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Increased effector memory insulin-specific CD4+ T cells correlate with insulin autoantibodies in patients with recent-onset type 1 diabetes. / Spanier, Justin A; Sahli, Nathanael L.; Wilson, Joseph C.; Martinov, Tijana; T, Dileepan; Burrack, Adam L.; Finger, Erik B; Blazar, Bruce R; Michels, Aaron W.; Moran, Antoinette; Jenkins, Marc; Fife, Brian T.

In: Diabetes, Vol. 66, No. 12, 01.12.2017, p. 3051-3060.

Research output: Contribution to journalArticle

Spanier, Justin A ; Sahli, Nathanael L. ; Wilson, Joseph C. ; Martinov, Tijana ; T, Dileepan ; Burrack, Adam L. ; Finger, Erik B ; Blazar, Bruce R ; Michels, Aaron W. ; Moran, Antoinette ; Jenkins, Marc ; Fife, Brian T. / Increased effector memory insulin-specific CD4+ T cells correlate with insulin autoantibodies in patients with recent-onset type 1 diabetes. In: Diabetes. 2017 ; Vol. 66, No. 12. pp. 3051-3060.
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