Role of the EHD Family of Endocytic Recycling Regulators for TCR Recycling and T Cell Function

J Immunol. 2018 Jan 15;200(2):483-499. doi: 10.4049/jimmunol.1601793. Epub 2017 Dec 6.

Abstract

T cells use the endocytic pathway for key cell biological functions, including receptor turnover and maintenance of the immunological synapse. Some of the established players include the Rab GTPases, the SNARE complex proteins, and others, which function together with EPS-15 homology domain-containing (EHD) proteins in non-T cell systems. To date, the role of the EHD protein family in T cell function remains unexplored. We generated conditional EHD1/3/4 knockout mice using CD4-Cre and crossed these with mice bearing a myelin oligodendrocyte glycoprotein-specific TCR transgene. We found that CD4+ T cells from these mice exhibited reduced Ag-driven proliferation and IL-2 secretion in vitro. In vivo, these mice exhibited reduced severity of experimental autoimmune encephalomyelitis. Further analyses showed that recycling of the TCR-CD3 complex was impaired, leading to increased lysosomal targeting and reduced surface levels on CD4+ T cells of EHD1/3/4 knockout mice. Our studies reveal a novel role of the EHD family of endocytic recycling regulatory proteins in TCR-mediated T cell functions.

Publication types

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

MeSH terms

  • Animals
  • CD3 Complex / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Carrier Proteins / genetics
  • DNA-Binding Proteins / genetics
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Endocytosis*
  • Female
  • Gene Expression
  • Gene Knockout Techniques
  • Lymphocyte Activation
  • Lymphoid Tissue / immunology
  • Lymphoid Tissue / metabolism
  • Lysosomes / metabolism
  • Mice
  • Mice, Knockout
  • Multigene Family
  • Multiprotein Complexes / metabolism
  • Nuclear Proteins / genetics
  • Protein Binding
  • Protein Transport
  • Proteolysis
  • Receptors, Antigen, T-Cell / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • CD3 Complex
  • Carrier Proteins
  • DNA-Binding Proteins
  • EHD4 protein, mouse
  • Ehd1 protein, mouse
  • Ehd3 protein, mouse
  • Multiprotein Complexes
  • Nuclear Proteins
  • Receptors, Antigen, T-Cell
  • Vesicular Transport Proteins