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Deranged Early T Cell Development in Immunodeficient Strains of Nonobese Diabetic Mice

Yui, Mary A. and Rothenberg, Ellen V. (2004) Deranged Early T Cell Development in Immunodeficient Strains of Nonobese Diabetic Mice. Journal of Immunology, 173 (9). pp. 5381-5391. ISSN 0022-1767. https://resolver.caltech.edu/CaltechAUTHORS:20170215-075718505

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Abstract

NOD mice exhibit defects in T cell functions that have been postulated to contribute to diabetes susceptibility in this strain. However, early T cell development in NOD mice has been largely unexplored. NOD mice with the scid mutation and Rag1 deficiency were analyzed for pre-T cell development in the NOD genetic background. These strains reveal an age-dependent, programmed breakdown in β selection checkpoint enforcement. At 5–8 wk of age, even in the absence of TCRβ expression, CD4^+ and CD4^+CD8^+ blasts appear spontaneously. However, these breakthrough cells fail to restore normal thymic cellularity. The breakthrough phenotype is recessive in hybrid (NOD×B6)F_1-scid and -Rag1^(null) mice. The breakthrough cells show a mosaic phenotype with respect to components of the β selection program. They mimic normal β selection by up-regulating germline TCR-Cα transcripts, CD2, and Bcl-x_L and down-regulating Bcl-2. However, they fail to down-regulate transcription factors HEB-alt and Hes1 and initially express aberrantly high levels of Spi-B, c-kit (CD117), and IL-7Rα. Other genes examined distinguish this form of breakthrough from previously reported models. Some of the abnormalities appear first in a cohort of postnatal thymocytes as early as the double-negative 2/double-negative 3 transitional stage. Thus, our results reveal an NOD genetic defect in T cell developmental programming and checkpoint control that permits a subset of the normal outcomes of pre-TCR signaling to proceed even in the absence of TCRβ rearrangement. Furthermore, this breakthrough may initiate thymic lymphomagenesis that occurs with high frequency in both NOD-scid and -Rag1^(null) mice.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.4049/jimmunol.173.9.5381DOIArticle
http://www.jimmunol.org/content/173/9/5381PublisherArticle
ORCID:
AuthorORCID
Yui, Mary A.0000-0002-3136-2181
Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2004 The American Association of Immunologists, Inc. Received for publication May 27, 2004. Accepted for publication August 12, 2004. We thank R. Bayon for excellent mouse care, R. Diamond and P. Koen (Caltech Flow Cytometry Facility) for advice and cell sorting, Dr. M. K. Anderson (University of Toronto) for Heb-alt primers, and Dr. E. Robey (University of California-Berkeley) for providing B6-Mhc^(null) mice. This work was supported by National Institutes of Health Grants AG13108 and CA90233 (to E.V.R.).
Funders:
Funding AgencyGrant Number
NIHAG13108
NIHCA90233
Issue or Number:9
Record Number:CaltechAUTHORS:20170215-075718505
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170215-075718505
Official Citation:Deranged Early T Cell Development in Immunodeficient Strains of Nonobese Diabetic Mice Mary A. Yui, Ellen V. Rothenberg The Journal of Immunology November 1, 2004, 173 (9) 5381-5391; DOI: 10.4049/jimmunol.173.9.5381
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74313
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:15 Feb 2017 16:50
Last Modified:03 Oct 2019 16:37

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