Attenuation of gammadeltaTCR signaling efficiently diverts thymocytes to the alphabeta lineage.
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.
Haks
Mariëlle C
MC
Division of Basic Sciences, Immunobiology Working Group, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Lefebvre
Juliette M
JM
Lauritsen
Jens Peter H
JP
Carleton
Michael
M
Rhodes
Michele
M
Miyazaki
Toru
T
Kappes
Dietmar J
DJ
Wiest
David L
DL
D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D051766:Early Growth Response Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D051796:Inhibitor of Differentiation Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D051796:Inhibitor of Differentiation Proteins; D011506:Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014157:Transcription Factors; C067679:Idb3 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases