Beta Cells Transfer Vesicles Containing Insulin to Phagocytes for Presentation to T Cells

Proc Natl Acad Sci U S A. 2015 Oct 6;112(40):E5496-502. doi: 10.1073/pnas.1515954112. Epub 2015 Aug 31.

Abstract

Beta cells from nondiabetic mice transfer secretory vesicles to phagocytic cells. The passage was shown in culture studies where the transfer was probed with CD4 T cells reactive to insulin peptides. Two sets of vesicles were transferred, one containing insulin and another containing catabolites of insulin. The passage required live beta cells in a close cell contact interaction with the phagocytes. It was increased by high glucose concentration and required mobilization of intracellular Ca2+. Live images of beta cell-phagocyte interactions documented the intimacy of the membrane contact and the passage of the granules. The passage was found in beta cells isolated from islets of young nonobese diabetic (NOD) mice and nondiabetic mice as well as from nondiabetic humans. Ultrastructural analysis showed intraislet phagocytes containing vesicles having the distinct morphology of dense-core granules. These findings document a process whereby the contents of secretory granules become available to the immune system.

Keywords: autoimmune diabetes; autoimmunity; insulin reactivity; insulin-reactive T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antigen Presentation / immunology
  • Calcium / metabolism
  • Cell Communication / drug effects
  • Cell Communication / immunology
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Extracellular Vesicles / immunology*
  • Extracellular Vesicles / metabolism
  • Extracellular Vesicles / ultrastructure
  • Female
  • Gene Expression / drug effects
  • Glucose / pharmacology
  • Heat-Shock Proteins / genetics
  • Humans
  • Insulin / immunology*
  • Insulin / metabolism
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / ultrastructure
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Microscopy, Fluorescence, Multiphoton
  • Phagocytes / immunology*
  • Phagocytes / metabolism
  • Phagocytes / ultrastructure
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Transcription Factor CHOP / genetics

Substances

  • Heat-Shock Proteins
  • Insulin
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • Transcription Factor CHOP
  • Egtazic Acid
  • Glucose
  • Calcium
  • molecular chaperone GRP78