Identification of a late stage of small noncycling pTalpha- pre-T cells as immediate precursors of T cell receptor alpha/beta+ thymocytes.
During thymocyte development, progression from T cell receptor (TCR)beta to TCRalpha rearrangement is mediated by a CD3-associated pre-TCR composed of the TCRbeta chain paired with pre-TCRalpha (pTalpha). A major issue is how surface expression of the pre-TCR is regulated during normal thymocyte development to control transition through this checkpoint. Here, we show that developmental expression of pTalpha is time- and stage-specific, and is confined in vivo to a limited subset of large cycling human pre-T cells that coexpress low density CD3. This restricted expression pattern allowed the identification of a novel subset of small CD3(-) thymocytes lacking surface pTalpha, but expressing cytoplasmic TCRbeta, that represent late noncycling pre-T cells in which recombination activating gene reexpression and downregulation of T early alpha transcription are coincident events associated with cell cycle arrest, and immediately preceding TCRalpha gene expression. Importantly, thymocytes at this late pre-T cell stage are shown to be functional intermediates between large pTalpha+ pre-T cells and TCRalpha/beta+ thymocytes. The results support a developmental model in which pre-TCR-expressing pre-T cells are brought into cycle, rapidly downregulate surface pre-TCR, and finally become small resting pre-T cells, before the onset of TCRalpha gene expression.
Centro de Biología Molecular "Severo Ochoa,".
C
C
Trigueros
A R
AR
Ramiro
Y R
YR
Carrasco
V G
VG
de Yebenes
J P
JP
Albar
M L
ML
Toribio
D000818:Animals; D017252:CD3 Complex / Q000032:analysis; D002453:Cell Cycle; D002675:Child, Preschool; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D007223:Infant; D051379:Mice; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis* / Q000235:genetics; D013601:T-Lymphocytes / Q000502:physiology*
D017252:CD3 Complex; D016693:Receptors, Antigen, T-Cell, alpha-beta