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Identification of a Late Stage of Small Noncycling pT^– Pre-T Cells as Immediate Precursors of T Cell Receptor /β⁺ Thymocytes

César Trigueros^*, Almudena R. Ramiro^*, Yolanda R. Carrasco^*, Virginia G. de Yebenes^*, Juan P. Albar, and María L. Toribio^*

From the ^* Centro de Biología Molecular "Severo Ochoa," and the Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain

During thymocyte development, progression from T cell receptor (TCR)β to TCR rearrangement is mediated by a CD3-associated pre-TCR composed of the TCRβ chain paired with pre-TCR (pT). 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 pT 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 pT, but expressing cytoplasmic TCRβ, that represent late noncycling pre-T cells in which recombination activating gene reexpression and downregulation of T early transcription are coincident events associated with cell cycle arrest, and immediately preceding TCR gene expression. Importantly, thymocytes at this late pre-T cell stage are shown to be functional intermediates between large pT⁺ pre-T cells and TCR/β⁺ 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 TCR gene expression.

Key Words: pre-T cells • pT • noncycling • recombination activating gene • T early

C. Trigueros and A.R. Ramiro contributed equally to this work.

Abbreviations used: DN, CD4^–CD8^– double negative; DP, CD4⁺CD8⁺ double positive; GFP, green fluorescent protein; PI, propidium iodide; pT, pre-TCR; RAG, recombination activating gene; RT, reverse transcription; SP, single positive; TEA, T early ; FSC, forward side scatter; FTOC, fetal thymic organ culture.

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