EphA receptors inhibit anti-CD3-induced apoptosis in thymocytes

J Immunol. 2006 Apr 1;176(7):4066-74. doi: 10.4049/jimmunol.176.7.4066.

Abstract

The EphA receptor tyrosine kinases interact with membrane-bound ligands of the ephrin-A subfamily. Interaction induces EphA receptor oligomerization, tyrosine phosphorylation, and, as a result, EphA receptor signaling. EphA receptors have been shown to regulate cell survival, migration, and cell-cell and cell-matrix interactions. However, their functions in lymphoid cells are only beginning to be described. We show in this study that functional EphA receptors are expressed by murine thymocytes, including CD4(+)CD8(+), CD4(+)CD8(-), and CD4(-)CD8(+) subpopulations. We demonstrate that activation of EphA receptors by the ephrin-A1 ligand inhibits the anti-CD3-induced apoptosis of CD4(+)CD8(+) double-positive thymocytes. Furthermore, ephrin-A1 costimulation suppresses up-regulation of both the IL-2R alpha-chain (CD25) and early activation Ag CD69 and can block IL-2 production by CD4(+) single-positive cells. In agreement, EphA receptor activation in thymocytes also inhibits TCR-induced activation of the Ras-MAPK pathway. Our findings suggest that EphA receptor activation is antithetical to TCR signaling in thymocytes, and that the level of engagement by ephrin-A proteins on thymic APCs regulates thymocyte selection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology*
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Apoptosis / drug effects
  • Apoptosis / immunology*
  • CD3 Complex / immunology*
  • Cells, Cultured
  • Ephrin-A1 / pharmacology
  • Female
  • Gene Expression Regulation
  • Interleukin-2 / metabolism
  • Lectins, C-Type
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinases / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Eph Family / immunology*
  • Receptors, Eph Family / metabolism*
  • Receptors, Interleukin-2 / metabolism
  • Thymus Gland / cytology*
  • Thymus Gland / drug effects
  • Thymus Gland / immunology*
  • Thymus Gland / metabolism
  • ras Proteins / metabolism

Substances

  • Antibodies
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD3 Complex
  • CD69 antigen
  • Ephrin-A1
  • Interleukin-2
  • Lectins, C-Type
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-2
  • Receptors, Eph Family
  • Mitogen-Activated Protein Kinases
  • ras Proteins