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

Xu, Yang and Davidson, Laurie and Alt, Frederick W. and Baltimore, David (1996) Function of the pre-T-cell receptor alpha chain in T-cell development and allelic exclusion at the T-cell receptor beta locus. Proceedings of the National Academy of Sciences of the United States of America, 93 (5). pp. 2169-2173. ISSN 0027-8424. PMCID PMC39929. doi:10.1073/pnas.93.5.2169.

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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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Baltimore, David0000-0001-8723-8190
Additional Information:© 1996 National Academy of Sciences. Contributed by David Baltimore, October 27, 1995. We thank Dennis Loh for the TCRBeta transgene. We also thank Drs. B. Sha, W. Pear, W. Swat, and J. Chen for helpful discussion and critically reading the manuscript. This work was supported by grants from the National Institutes of Health. Y.X. was supported by the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation Fellowship, DRG-1317; D.B. is an American Cancer Society Research professor. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Funding AgencyGrant Number
Damon Runyon-Walter Winchell Cancer FundDRG-1317
American Cancer SocietyUNSPECIFIED
Subject Keywords:gene targeting, T-cell differentiation, allelic exclusion, transgenic mice, targeted disruption, immunoglobulin-mu, membrane exon, genes, expression, antigen, mutations, protein, rag-2
Issue or Number:5
PubMed Central ID:PMC39929
Record Number:CaltechAUTHORS:XUYpnas96
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:887
Deposited By: Tony Diaz
Deposited On:01 Nov 2005
Last Modified:08 Nov 2021 19:05

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