RasGRP1 Transmits Prodifferentiation TCR Signaling That Is Crucial for CD4 T Cell Development

• Published in: Journal of Immunology Vol. 177; no. 3; pp. 1470 - 1480
• Main Authors: Priatel, John J, Chen, Xiaoxi, Dhanji, Salim, Abraham, Ninan, Teh, Hung-Sia
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.08.2006
• Subjects: Animals; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - enzymology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Survival - genetics; Cell Survival - immunology; Guanine Nucleotide Exchange Factors - deficiency; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - physiology; Histocompatibility Antigens Class II - physiology; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; ras Proteins - genetics; ras Proteins - physiology; Receptors, Antigen, T-Cell - antagonists & inhibitors; Receptors, Antigen, T-Cell - biosynthesis; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - physiology; T-Lymphocytes, Cytotoxic - cytology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Thymus Gland - cytology; Thymus Gland - enzymology; Thymus Gland - immunology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.177.3.1470

TCR signaling plays a governing role in both the survival and differentiation of bipotent double-positive thymocytes into the CD4(+) and CD8(+) single-positive T cell lineages. A central mediator of this developmental program is the small GTPase Ras, emitting cytoplasmic signals through downstream MAPK pathways and eventually affecting gene expression. TCR signal transduction orchestrates the activation of Ras by integrating at least two Ras-guanyl nucleotide exchange factors, RasGRP1 and Sos. In this study, we have characterized the relationship between RasGRP1 function and its potential roles in promoting ERK activity, cell survival, maturation, and lineage commitment. Investigations on RasGRP1(-/-) mice expressing a transgenic (Tg) MHC class II-restricted TCR revealed that the development of CD4 T cells expressing this Tg TCR is completely dependent on RasGRP1. Unexpectedly, a small number of functional CD8 single-positive thymocytes expressing the Tg MHC class II-restricted TCR exists in mutant mice. In addition, RasGRP1(-/-) double-positive thymocytes exhibit marked deficits in TCR-stimulated up-regulation of the positive selection marker CD69 and the antiapoptotic protein Bcl-2, whereas CD5 induction is unaffected. To evaluate the role of RasGRP1 in providing cellular survival signaling, we enforced Bcl-2 expression in RasGRP1(-/-) thymocytes. These studies demonstrate that RasGRP1 function cannot be fully complemented by Tg Bcl-2 expression. Therefore, we propose that RasGRP1 transmits differentiation signaling critically required for CD4 T cell development.