{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T07:42:48Z","timestamp":1789976568223,"version":"4.0.1"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2004,11,1]],"date-time":"2004-11-01T00:00:00Z","timestamp":1099267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2004,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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 \u03b2 selection checkpoint enforcement. At 5\u20138 wk of age, even in the absence of TCR\u03b2 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\u00d7B6)F1-scid and -Rag1null mice. The breakthrough cells show a mosaic phenotype with respect to components of the \u03b2 selection program. They mimic normal \u03b2 selection by up-regulating germline TCR-C\u03b1 transcripts, CD2, and Bcl-xL 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-7R\u03b1. 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 TCR\u03b2 rearrangement. Furthermore, this breakthrough may initiate thymic lymphomagenesis that occurs with high frequency in both NOD-scid and -Rag1null mice.<\/jats:p>","DOI":"10.4049\/jimmunol.173.9.5381","type":"journal-article","created":{"date-parts":[[2014,4,21]],"date-time":"2014-04-21T00:56:18Z","timestamp":1398041778000},"page":"5381-5391","source":"Crossref","is-referenced-by-count":24,"title":["Deranged Early T Cell Development in Immunodeficient Strains of Nonobese Diabetic Mice"],"prefix":"10.1093","volume":"173","author":[{"given":"Mary A","family":"Yui","sequence":"first","affiliation":[{"name":"Division of Biology, California Institute of Technology , Pasadena, CA 91125"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen V","family":"Rothenberg","sequence":"additional","affiliation":[{"name":"Division of Biology, California Institute of Technology , Pasadena, CA 91125"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2004,11,1]]},"reference":[{"key":"2025032707162284100_R1","first-page":"179","volume-title":"Annu. 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