ABSTRACT
The magnitude of T cell responses is determined by proliferation and survival decisions made by the responding cells. We now demonstrate that the Erk MAPK pathway plays a critical role in these cell fate decisions within CD8 T cells. While Erk1 is dispensable for all aspects of CD8 T cell activation, Erk2 is required for the proliferation of CD8 T cells activated in the absence of costimulation. Surprisingly, Erk2 is not required for proliferation following the addition of a costimulatory signal in vitro, or upon viral infection in vivo, but regulates the size of the responding population by enhancing cell survival. An important component of this Erk2-derived signal is the transcriptional regulation of Bcl-2 family members Bcl-x(L) and Bim, and impaired Erk2-deficient CD8 T cell survival can be rescued by genetic ablation of Bim. These studies ascribe multifaceted functions specific to Erk2 in CD8 T cell activation, proliferation, and survival.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cell Proliferation , Lymphocyte Activation/immunology , MAP Kinase Signaling System/immunology , Mitogen-Activated Protein Kinase 1/immunology , Animals , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/immunology , Apoptosis Regulatory Proteins/metabolism , Bcl-2-Like Protein 11 , CD8-Positive T-Lymphocytes/enzymology , Cell Survival/genetics , Cell Survival/immunology , Lymphocyte Activation/genetics , MAP Kinase Signaling System/genetics , Membrane Proteins/genetics , Membrane Proteins/immunology , Membrane Proteins/metabolism , Mice , Mice, Knockout , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/genetics , Mitogen-Activated Protein Kinase 3/immunology , Mitogen-Activated Protein Kinase 3/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/immunology , Proto-Oncogene Proteins/metabolism , Transcription, Genetic/genetics , Transcription, Genetic/immunology , bcl-X Protein/genetics , bcl-X Protein/immunology , bcl-X Protein/metabolismABSTRACT
Activation of extracellular-signal-regulated protein kinase (Erk) is central to growth-factor-receptor-mediated signaling including that originating from the T cell antigen receptor. It integrates cytoplasmic signals to effect changes in transcription associated with differentiation, proliferation, and survival. In this report, we present an analysis of mice with targeted deletions in Erk1 and Erk2 to assess the relationship between Erk activity and cell-cycle progression, thymocyte development, and lineage commitment. These studies show that Erk is selectively retained during beta selection-driven proliferation, and yet Erk1/2 are not required to complete differentiation to CD4+CD8+ preselection stage of development. Erk activity is essential for the process of positive selection, and it differentially affects CD4 and CD8 T cell maturation; yet, diminished expression itself is not sufficient to alter lineage commitment.
