Abstract
Bone marrow (BM)-derived T-cell progenitors differentiate into CD4 or CD8 single-positive (SP) cells in the thymus. We have previously reported that a single autosomal mutation, thid, causes a defect in the maturation of CD4 SP thymocytes and an abnormality of peripheral helper T cells in the LEC rat. In this study we attempted to identify a gene responsible for the thid mutation. We first performed genetic linkage analysis and mapped the thid locus between Myb and D1Rat392 on Chr 1. In this region we found an approximately 380-kb deletion from intron 3 of the Ptprk gene, which encodes a receptor-like protein tyrosine phosphatase type κ (RPTPκ) to intron 1 of the RGD1560849 predicted gene in the LEC rat genome. Reconstitution with syngenic BM cells transduced Ptprk but not the RGD1560849 predicted gene rescued development of CD4 SP cells in the LEC rat thymus. It is confirmed by this result that the Ptprk gene is responsible for the thid mutation in the LEC rat. Our results further suggest that RPTPκ plays a critical role in the development of CD4 SP cells in the thymus.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Agui T, Oka M, Yamada T, Sakai T, Izumi K, et al. (1990) Maturational arrest from CD4+8+ to CD4+8- thymocytes in a mutant strain (LEC) of rat. J Exp Med 172:1615–1624
Agui T, Sakai T, Himeno K, Matsumoto K (1991a) Bone marrow-derived progenitor T cells convey the origin of maturational arrest from CD4+CD8+ to CD4+CD8- thymocytes in LEC mutant rats. Eur J Immunol 21:2277–2280
Agui T, Sakai T, Matsumoto K (1991b) Ontogeny of T cell maturation in LEC mutant rats which bear a congenital arrest of maturation from CD4+CD8+ to CD4+CD8- thymocytes. Eur J Immunol 21:2537–2541
Alonso A, Sasin J, Bottini N, Friedberg I, Osterman A, et al. (2004) Protein tyrosine phosphatases in the human genome. Cell 117:699–711
Bousso P, Bhakta NR, Lewis RS, Robey E (2002) Dynamics of thymocyte-stromal cell interactions visualized by two-photon microscopy. Science 296:1876–1880
Cooney KA, Wetzel JC, Consolino CM, Wonjo KJ (1996) Identification and characterization of proximal 6q deletion in prostate cancer. Cancer Res 56:4150–4153
Gallegos AM, Bevan MJ (2004) Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J Exp Med 200:1039–1049
Hayashi M, Okui T, Endoh D, Sato F, Kasai N, et al. (1994) Radiation hypersensitivity of LEC strain rats controlled by a single autosomal recessive gene. Mutat Res 314:135–142
He X, Dave VP, Zhang Y, Hua X, Nicolas E, et al. (2005) The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment. Nature 433:826–833
Jiang YP, Wang H, D’Eustachio P, Musacchio JM, Schlessinger J, et al. (1993) Cloning and characterization of R-PTP-kappa, a new member of the receptor protein tyrosine phosphatase family with a proteolytically cleaved cellular adhesion molecule-like extracellular region. Mol Cell Biol 13:2942–2951
Jung C-G, Miyamoto T, Tsumagari T, Agui T (2001) Genetic association between low expression phenotype of CD62L (L-selectin) in peripheral CD4+ T cells and the thid (T-helper immunodeficiency) phenotype in the LEC rat. Exp Anim 50:337–340
Koop EA, Lopes SM, Feiken E, Bluyssen HA, van der Valk M, et al. (2003) Receptor protein tyrosine phosphatase mu expression as a marker for endothelial cell heterogeneity; analysis of RPTPmu gene expression using LacZ knock-in mice. Int J Dev Biol 47:345–354
Kose H, Sakai T, Tsukumo S, Wei K, Yamada T, et al. (2007) Maturational arrest of thymocyte development is caused by a deletion in the receptor-like protein tyrosine phosphatase κ gene in LEC rats. Genomics 89:673–677
Ladi E, Yin X, Chtanova T, Robey EA (2006) Thymic microenvironments for T cell differentiation and selection. Nat Immunol 7:338–343
Laky K, Fleischacker C, Fowlkes B (2006) TCR and Notch signaling in CD4 and CD8 T-cell development. Immunol Rev 209:274–283
Lind EF, Prockop SE, Porritt HE, Petrie HT (2001) Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J Exp Med 194:127–134
Liu X, Bosselut R (2004) Duration of TCR signaling controls CD4-CD8 lineage differentiation in vivo. Nat Immunol 5:280–288
Manly KF, Cudmore RH Jr, Meer JM (2001) Map Manager QTX, cross-platform software for genetic mapping. Mamm Genome 12:930–932
McArdle L, Rafferty M, Mælandsmo GM, Bergin O, Farr CJ, et al. (2001) Protein tyrosine phosphatase genes downregulated in melanoma. J Invest Dermatol 117:1255–1260
Nakamura M, Kishi M, Sakaki T, Hashimoto H, Nakase H, et al. (2003) Novel tumor suppressor loci on 6q22-23 in primary central nervous system lymphomas. Cancer Res 63:737–741
Porritt HE, Gordon K, Petrie HT (2003) Kinetics of steady-state differentiation and mapping of intrathymic-signaling environments by stem cell transplantation in nonirradiated mice. J Exp Med 198:957–962
Sakai T, Agui T, Muramatsu Y, Yamada T, Matsumoto K (1993) Dissociation of the interleukin-2 production from the cell activation in response to the mitogenic lectin in peripheral CD4+ cells of LEC mutant rats. Immunology 79:491–497
Sap J, Jiang YP, Friedlander D, Grumet M, Schlessinger J (1994) Receptor tyrosine phosphatase R-PTP-kappa mediates homophilic binding. Mol Cell Biol 14:1–9
Shen P, Canoll P, Sap J, Musacchio JM (1999) Expression of a truncated receptor protein tyrosine phosphatase kappa in the brain of an adult transgenic mouse. Brain Res 826:157–171
Siggs OM, Makaroff LE, Liston A (2006) The why and how of thymocyte negative selection. Curr Opin Immunol 18:175–183
Singer A, Bosselut R (2004) CD4/CD8 coreceptors in thymocyte development, selection, and lineage commitment: analysis of the CD4/CD8 lineage decision. Adv Immunol 83:91–131
Skarnes WC, Moss JM, Hurtley SM, Beddington RS (1995) Capturing genes encoding membrane and secreted proteins important for mouse development. Proc Natl Acad Sci USA 92:6592–6596
Sun G, Liu X, Mercado P, Jenkinson SR, Kypriotou M, et al. (2005) The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection. Nat Immunol 6:373–381
Theile M, Seitz S, Arnold W, Jandrig B, Frege R, et al. (1996) A defined chromosome 6q fragment (at D6S310) harbors a putative tumor suppressor gene for breast cancer. Oncogene 13:677–685
Wang SE, Wu FY, Shin I, Qu S, Arteaga CL (2005) Transforming growth factor β (TGF-β)-Smad target gene protein tyrosine phosphatase receptor type kappa is required for TGF-β function. Mol Cell Biol 25:4703–4715
Wei K, Muramatsu Y, Sakai T, Yamada T, Matsumoto K (1997) Chromosomal mapping of the T-helper immunodeficiency (thid) locus in LEC rats. Immunogenetics 47:99–102
Witt CM, Raychaudhuri S, Schaefer B, Chakraborty AK, Robey EA (2005) Directed migration of positively selected thymocytes visualized in real time. PLoS Biol 3:e160
Yamada T, Natori T, Izumi K, Sakai T, Agui T, et al. (1991) Inheritance of T-helper immunodeficiency (thid) in LEC mutant rats. Immunogenetics 33:216–219
Yang Y, Gil MC, Choi EY, Park SH, Pyun KH, et al. (1997) Molecular cloning and chromosomal localization of a human gene homologous to the murine R-PTP-kappa, a receptor-type protein tyrosine phosphatase. Gene 186:77–82
Zondag GC, Koningstein GM, Jiang YP, Sap J, Moolenaar WH, et al. (1995) Homophilic interactions mediated by receptor tyrosine phosphatases mu and kappa. A critical role for the novel extracellular MAM domain. J Biol Chem 270:14247–14250
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Asano, A., Tsubomatsu, K., Jung, CG. et al. A deletion mutation of the protein tyrosine phosphatase kappa (Ptprk) gene is responsible for T-helper immunodeficiency (thid) in the LEC rat. Mamm Genome 18, 779–786 (2007). https://doi.org/10.1007/s00335-007-9062-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-007-9062-0