Costimulatory signals are required for induction of transcription factor Nur77 during negative selection of CD4(+)CD8(+) thymocytes.
A major question in end-stage T cell development is how T cell receptor(TCR) ligation on immature CD4(+)CD8(+) double positive thymocytes is translated into either survival (positive selection) or apoptotic (negative selection) signals. Because different types of antigen-presenting cells (APCs) induce positive or negative selection in the thymus and express different costimulatory molecules, involvement of such costimulatory molecules in determining cell fate of DP thymocytes is considered here. If TCR-generated signals are modulated by APCs, this should be reflected in the activation of distinct biochemical pathways. We here demonstrate that costimulatory signals involved in negative selection also are required for induction of protein expression of Nur77 and its family members. These transcription factors are critically involved in negative but not positive selection. In contrast, the signals that costimulate negative selection are not required for induction of several molecular events associated with positive selection. These include activation of the immediate early gene Egr-1, the mitogen-activated protein kinase ERK2, and surface expression of the CD69 marker. Thus, costimulation for negative selection selectively provides signals for activation of apoptotic mediators. These data provide molecular insights into how TCR-engagement by ligands on different thymic APCs can determine cell fate.
Amsen
D
D
Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Revilla Calvo
C
C
Osborne
B A
BA
Kruisbeek
A M
AM
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D051766:Early Growth Response Protein 1; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D017874:Immediate-Early Proteins; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015398:Signal Transduction / Q000235:genetics*; D013950:Thymus Gland / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics*
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011948:Receptors, Antigen, T-Cell; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1