Costimulatory Signals Are Required for Induction of Transcription Factor Nur77 during Negative Selection of CD4+CD8+Thymocytes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 2; pp. 622 - 627
• Main Authors: Amsen, Derk, Calvo, Conchi Revilla, Osborne, Barbara A., Kruisbeek, Ada M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 19.01.1999; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Antibodies; Antigen-Presenting Cells - immunology; Antigens, CD - immunology; Apoptosis; Biochemistry; Biological Sciences; Calcium-Calmodulin-Dependent Protein Kinases - genetics; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Cellular biology; Clonal deletion; DNA-Binding Proteins - genetics; Early Growth Response Protein 1; Flow Cytometry; Gene Expression Regulation - immunology; Immediate-Early Proteins; Immunology; Ligands; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Molecules; Negative selection; Nuclear Receptor Subfamily 4, Group A, Member 1; Positive selection; Protein synthesis; Receptors, Antigen, T-Cell - immunology; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Signal Transduction - genetics; T cell antigen receptors; Thymocytes; Thymus Gland - immunology; Transcription Factors - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.2.622

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 antigenpresenting 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 APC's can determine cell fate.