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T Cell Development from Kit-Negative Progenitors in the Foxn1^/ Mutant Thymus¹

Department of Genetics, Coverdell Center, University of Georgia, Athens, GA 30602

Foxn1 is a hypomorphic allele of the nude gene that causes arrested thymic epithelial cell differentiation and abnormal thymic architecture lacking cortical and medullary domains. T cells develop in the Foxn1^/ adult thymus to the double- and single-positive stages, but in the apparent absence of double-negative 3 (DN3) cells; however, DN3 cells are present in the fetal thymus. To investigate the origin of this seemingly contradictory phenotype, we performed an analysis of fetal and adult DN cells in these mutants. Neither adult bone marrow-derived cells nor fetal liver cells from wild-type or Rag1^–/– mice were able to differentiate to the DN2 or DN3 stage in the Foxn1^/ thymus. Our data suggest that thymopoiesis in the Foxn1^/ adult thymus proceeds from CD117^– atypical progenitors, while CD117⁺ DN1a cells are absent or blocked in their ability to differentiate to the T lineage. Wild-type cells generated by this pathway in the postnatal thymus were exported to the periphery, demonstrating that these atypical cells contributed to the peripheral T cell pool. The Foxn1^/ adult (but not fetal) thymus also preferentially supports B cell development, specifically of the B-1 type, and this phenotype correlated with reduced Notch ligand expression in the adult stroma.

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¹ This work was supported by National Institutes of Health, National Institute of Allergy and Infectious Disease Grant AI055001 (to N.R.M.).

² Current address: Department of Biomedical Research, University of Texas Health Center, Tyler, TX 75708.

³ Address correspondence and reprint requests to Dr. Nancy R. Manley, Department of Genetics, S270 Coverdell Center for Biomedical and Health Sciences, University of Georgia, Athens, GA 30602. E-mail address: nmanley{at}uga.edu

⁴ Abbreviations used in this paper: BM, bone marrow; TEC, thymic epithelial cell; DN, double negative; SP, single positive; DP, double positive; FL, fetal liver; FTOC, fetal thymic organ culture.