EphA receptors inhibit anti-CD3-induced apoptosis in thymocytes.
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.
Department of Chemistry and Biochemistry, University of Regina, Saskatchewan, Canada.
Andrew
A
Freywald
Nigel
N
Sharfe
Charlotte D'E
CD
Miller
Cher
C
Rashotte
Chaim M
CM
Roifman
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D002478:Cells, Cultured; D036382:Ephrin-A1 / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D007376:Interleukin-2 / Q000378:metabolism; D037181:Lectins, C-Type; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D036081:Receptors, Eph Family / Q000276:immunology* / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D000099192:CD69 Antigens
D000906:Antibodies; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D036382:Ephrin-A1; D007376:Interleukin-2; D037181:Lectins, C-Type; D020928:Mitogen-Activated Protein Kinases; D011948:Receptors, Antigen, T-Cell; D036081:Receptors, Eph Family; D015375:Receptors, Interleukin-2; D018631:ras Proteins; D000099192:CD69 Antigens