Attenuation of gammadeltaTCR signaling efficiently diverts thymocytes to the alphabeta lineage

Immunity. 2005 May;22(5):595-606. doi: 10.1016/j.immuni.2005.04.003.

Abstract

The role of the T cell antigen receptor complex (TCR) in alphabeta/gammadelta lineage commitment remains controversial, in particular whether different TCR isoforms intrinsically favor adoption of a certain lineage. Here, we demonstrate that impairing the signaling capacity of a gammadeltaTCR complex enables it to efficiently direct thymocytes to the alphabeta lineage. In the presence of a ligand, a transgenic gammadeltaTCR mediates almost exclusive adoption of the gammadelta lineage, while in the absence of ligand, the same gammadeltaTCR promotes alphabeta lineage development with efficiency comparable to the pre-TCR. Importantly, attenuating gammadeltaTCR signaling through Lck deficiency causes reduced ERK1/2 activation and Egr expression and diverts thymocytes to the alphabeta lineage even in the presence of ligand. Conversely, ectopic Egr overexpression favors gammadelta T cell development. Our data support a model whereby gammadelta versus alphabeta lineage commitment is controlled by TCR signal strength, which depends critically on the ERK MAPK-Egr pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • Early Growth Response Protein 1
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Immediate-Early Proteins / biosynthesis
  • Immediate-Early Proteins / genetics
  • Inhibitor of Differentiation Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphorylation
  • Proteins / genetics
  • Proteins / metabolism
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism*
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Signal Transduction
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocyte Subsets / immunology*
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics

Substances

  • DNA-Binding Proteins
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Immediate-Early Proteins
  • Inhibitor of Differentiation Proteins
  • Proteins
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Antigen, T-Cell, gamma-delta
  • Transcription Factors
  • Idb3 protein, mouse
  • Extracellular Signal-Regulated MAP Kinases