Function of the pre-T-cell receptor alpha chain in T-cell development and allelic exclusion at the T-cell receptor beta locus

Abstract

The pre-T-cell receptor, composed of the T-cell receptor (TCR) beta chain (TCR beta), pre-T alpha (pT alpha) chain, and CD3 molecules, has been postulated to be a transducer of signals during the early stages of T-cell development. To examine the function of the transmembrane pT alpha chain during thymocyte development, we generated pT alpha(-/-) embryonic stem cells and assayed their ability to differentiate into lymphoid cells in vivo after injection into recombination-activating gene (RAG)-2-deficient blastocysts. Thymocytes representing all stages of T-cell differentiation were detected in the thymus of pT alpha(-/-) chimeric mice, indicating that thymocyte development can occur without pT alpha. However, greatly reduced thymocyte numbers and substantially increased percentages of both CD4(-)CD8(-) thymocytes and TCR gamma delta(+) thymocytes suggest that pT alpha plays a critical role in thymocyte expansion. To investigate the role of the pT alpha chain in allelic exclusion at the TCR beta locus, a functionally rearranged TCR beta minigene was introduced into pT alpha(-/-) and pT alpha(+/-) embryonic stem cells, which were subsequently assayed by RAG-2-deficient blastocyst complementation. In the absence of pT alpha, expression of the transgenic TCR beta inhibited rearrangement of the endogenous TCR beta locus to an extent similar to that seen in normal TCR beta transgenic mice, suggesting that pT alpha may not be required for signaling allelic exclusion at the TCR beta locus.

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