Deranged early T cell development in immunodeficient strains of nonobese diabetic mice.
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 beta selection checkpoint enforcement. At 5-8 wk of age, even in the absence of TCRbeta 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 (NODxB6)F1-scid and -Rag1null mice. The breakthrough cells show a mosaic phenotype with respect to components of the beta selection program. They mimic normal beta selection by up-regulating germline TCR-Calpha 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-7Ralpha. 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 TCRbeta rearrangement. Furthermore, this breakthrough may initiate thymic lymphomagenesis that occurs with high frequency in both NOD-scid and -Rag1null mice.
Yui
Mary A
MA
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Rothenberg
Ellen V
EV
D000375:Aging / Q000235:genetics / Q000276:immunology; D000818:Animals; D018801:CD2 Antigens / Q000096:biosynthesis / Q000235:genetics; D015704:CD4 Antigens / Q000096:biosynthesis; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D016654:Genes, RAG-1; D005808:Genes, Recessive; D019673:Genes, T-Cell Receptor alpha; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000276:immunology; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D018801:CD2 Antigens; D015704:CD4 Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D020395:Receptors, Interleukin-7; D051020:bcl-X Protein; C415350:interleukin-7 receptor, alpha chain; D019009:Proto-Oncogene Proteins c-kit