Detection and Characterization of CD8 + Autoreactive Memory Stem T Cells in Patients With Type 1 Diabetes

Diabetes. 2018 May;67(5):936-945. doi: 10.2337/db17-1390. Epub 2018 Mar 5.

Abstract

Stem memory T cells (Tscm) constitute the earliest developmental stage of memory T cells, displaying stem cell-like properties, such as self-renewal capacity. Their superior immune reconstitution potential has sparked interest in cancer immune therapy, vaccine development, and immune reconstitution, whereas their role in autoimmunity is largely unexplored. Here we show that autoreactive CD8+ Tscm specific for β-cell antigens GAD65, insulin, and IGRP are present in patients with type 1 diabetes (T1D). In vitro, the generation of autoreactive Tscm from naive precursors required the presence of the homeostatic cytokine interleukin-7 (IL-7). IL-7 promotes glucose uptake via overexpression of GLUT1 and upregulation of the glycolytic enzyme hexokinase 2. Even though metabolism depends on glucose uptake, the subsequent oxidation of pyruvate in the mitochondria was necessary for Tscm generation from naive precursors. In patients with T1D, high expression of GLUT1 was a hallmark of circulating Tscm, and targeting glucose uptake via GLUT1 using the selective inhibitor WZB117 resulted in inhibition of Tscm generation and expansion. Our results suggest that autoreactive Tscm are present in patients with T1D and can be selectively targeted by inhibition of glucose metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autoimmunity / immunology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Child
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Female
  • Glucose / metabolism
  • Glucose Transporter Type 1 / metabolism
  • Glucose-6-Phosphatase / immunology
  • Glutamate Decarboxylase / immunology
  • Hexokinase / metabolism
  • Humans
  • Hydroxybenzoates / pharmacology
  • Immunologic Memory / immunology
  • In Vitro Techniques
  • Insulin / immunology
  • Interleukin-7 / immunology
  • Lymphoid Progenitor Cells / immunology*
  • Lymphopoiesis / drug effects
  • Male
  • Middle Aged
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • Up-Regulation

Substances

  • Glucose Transporter Type 1
  • Hydroxybenzoates
  • IL7 protein, human
  • Insulin
  • Interleukin-7
  • SLC2A1 protein, human
  • WZB117
  • HK2 protein, human
  • Hexokinase
  • Glucose-6-Phosphatase
  • G6PC2 protein, human
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2
  • Glucose