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EphA Receptors Inhibit Anti-CD3-Induced Apoptosis in Thymocytes¹

Andrew Freywald^2,*, Nigel Sharfe^2,, Charlotte D’E. Miller, Cher Rashotte and Chaim M. Roifman^3,

^* Department of Chemistry and Biochemistry, University of Regina, Saskatchewan, Canada; and Immunology and Allergy, Department of Pediatrics, Infection, Immunity, Injury, and Repair Program, Research Institute, Hospital for Sick Children, and University of Toronto, Toronto, Ontario, Canada

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 -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.