Unresponsiveness of CD4<sup>−</sup>8<sup>+/−</sup> thymocytes to lectin stimulation in LEC mutant rats

Sakai,; Agui,; Kaichun,; Oka,; Hisaeda,; Nagasawa, Kazuya; Himeno,; Matsumoto, Tadahiko

doi:10.1046/j.1365-2567.1998.00574.x

Cited by 5 publications

(3 citation statements)

References 35 publications

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“…A decrease in CD4 lineage T cells is a common phenotype seen in LEC rats (14) and themis-deficient mice, but a decrease in CD8 T cells is seen only in the themis-deficient mice. However, since the reduction of CD8 T cells in these mice is not as prominent as the CD4 T-cell defect, it is probable that this phenotype is masked in LEC rats through unknown compen- FIG.…”

Section: Vol 29 2009 Gene Essential For Single Positive Thymocytes mentioning

confidence: 95%

“…5A). LEC rats are known to have a reduction in CD4 SP T cells in the thymus and periphery, resulting in a defective immune response, a phenotype designated thid (for T helper immunodeficiency), which is inherited in an autosomal recessive manner (14). Two independent studies reported that the large genomic deletion that eliminates ptpr and RGD1560849 (the rat analog of E430004N04Rik) function causes the thid phenotype.…”

Section: Vol 29 2009 Gene Essential For Single Positive Thymocytes mentioning

confidence: 99%

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A Novel Gene Essential for the Development of Single Positive Thymocytes

Kakugawa

Yasuda

Miura

et al. 2009

Molecular and Cellular Biology

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A critical step during intrathymic T-cell development is the transition of CD4؉ CD8 ؉ double-positive (DP) cells to the major histocompatibility complex class I (MHC-I)-restricted CD4؊ CD8 ؉ and MHC-II-restricted CD4 ؉ CD8 ؊ single-positive (SP) cell stage. Here, we identify a novel gene that is essential for this process. Through the T-cell phenotype-based screening of N-ethyl-N-nitrosourea (ENU)-induced mutant mice, we established a mouse line in which numbers of CD4 and CD8 SP thymocytes as well as peripheral CD4 and CD8 T cells were dramatically reduced. Using linkage analysis and DNA sequencing, we identified a missense point mutation in a gene, E430004N04Rik (also known as themis), that does not belong to any known gene family. This orphan gene is expressed specifically in DP and SP thymocytes and peripheral T cells, whereas in mutant thymocytes the levels of protein encoded by this gene were drastically reduced. We generated E430004N04Rik-deficient mice, and their phenotype was virtually identical to that of the ENU mutant mice, thereby confirming that this gene is essential for the development of SP thymocytes.The differentiation step from the double-positive (DP) to single-positive (SP) thymocyte stage is critically regulated by signals originating from the T-cell receptor ␣/␤ (TCR␣/␤) expressed on their surface (3,5,16,17). By using reverse genetic approaches by knocking out or overexpressing various genes that are expected to be involved in TCR signaling, including its ligand major histocompatibility complex molecules and coreceptors CD4 and CD8, the roles of these genes in T-cell development have been investigated intensively (11,12). However, to identify totally unknown mechanisms in T-cell development, the forward genetic approach is required. Nethyl-N-nitrosourea (ENU) is a potent mutagen that randomly induces point mutations throughout the genome in a dosedependent manner, and ENU mutagenesis has been a representative forward genetic strategy (4, 15). We have been screening phenotypes of ENU-mutagenized mice, focusing on defects in T-cell development. MATERIALS AND METHODSMice. C57BL/6 (B6) and B6Ly5.1 congenic mice were purchased from CLEA Japan, Inc. All mice were maintained in the animal facility at the RIKEN Research Center for Allergy and Immunology, and all experiments were done in accordance with institutional guidelines for animal care. ENU mutagenesis. ENU was administered to male C57BL/6J mice, and their sperm was mated to wild-type eggs and preserved as founder embryos (8, 21) for use in our screening.Mapping and sequencing. Phenodeviants that showed CD3 ϩ cell reduction were crossed to wild-type C3H/HeJ mice to test for phenotype transmission and for the genetic mapping of the causative genes. Single-nucleotide polymorphism (SNP) mapping was performed as described elsewhere (13). For sequencing, we focused on the ptprk and E430004N04Rik genes, which were among candidate genes listed by PosMed (21) (http://omicspace.riken.jp). cDNA and genomic DNA were amplified by PCR and sequenced us...

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Section: Vol 29 2009 Gene Essential For Single Positive Thymocytes mentioning

confidence: 95%

Section: Vol 29 2009 Gene Essential For Single Positive Thymocytes mentioning

confidence: 99%

A Novel Gene Essential for the Development of Single Positive Thymocytes

Kakugawa

Yasuda

Miura

et al. 2009

Molecular and Cellular Biology

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“…In addition, peripheral CD4 ϩ T cells of LEC rats were shown not to function as Th cells in Ab production against T cell-dependent Ag and IL-2 production by polyclonal stimulation (32,33). However, it remains unclear whether the T cell dysfunction of LEC rats might have an influence on any disease associated with the immune disorder.…”

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confidence: 99%

Development of Inflammatory Bowel Disease in Long-Evans Cinnamon Rats Based on CD4+CD25+Foxp3+ Regulatory T Cell Dysfunction

Ishimaru

Yamada

Kohashi

et al. 2008

The Journal of Immunology

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A mutant strain with defective thymic selection of the Long-Evans Cinnamon (LEC) rat was found to spontaneously develop inflammatory bowel disease (IBD)-like colitis. The secretion of Th1-type cytokines including IFN-γ and IL-2 from T cells of mesenteric lymph node cells (MLNs) and lamina propria mononuclear cells, but not spleen cells, in LEC rats was significantly increased more than that of the control Long-Evans Agouti rats through up-regulated expression of T-bet and phosphorylation of STAT-1 leading to NF-κB activation. In addition, the number of CD4+CD25+Foxp3+ regulatory T (Treg) cells of the thymus, MLNs, and lamina propria mononuclear cells from LEC rats was significantly reduced, comparing with that of the control rats. Moreover, bone marrow cell transfer from LEC rats into irradiated control rats revealed significantly reduced CD25+Foxp3+ Treg cells in thymus, spleen, and MLNs compared with those from control rats. Indeed, adoptive transfer with T cells of MLNs, not spleen cells, from LEC rats into SCID mice resulted in the development of inflammatory lesions resembling the IBD-like lesions observed in LEC rats. These results indicate that the dysfunction of the regulatory system controlled by Treg cells may play a crucial role in the development of IBD-like lesions through up-regulated T-bet, STAT-1, and NF-κB activation of peripheral T cells in LEC rats.

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Maturational arrest of thymocyte development is caused by a deletion in the receptor-like protein tyrosine phosphatase κ gene in LEC rats

et al. 2007

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The Long-Evans Cinnamon (LEC) rat has a spontaneous mutation, T helper immunodeficiency (thid), which causes a markedly reduced CD4(+) thymocyte population. Here we positionally clone the locus and identify a deletion in the gene encoding a receptor-like protein tyrosine phosphatase kappa (Ptprk) that led to complete loss of the transcript. The rat Ptprk gene exhibits 98% identity with the human and mouse counterparts and is expressed most abundantly in the CD4(-)CD8(-) double-negative stage. The downregulation of Ptprk in mouse immature thymocytes by RNA interference mimicked the thid phenotype. These results indicate that thid maps to the Ptprk locus and that functional Ptprk is crucial for lineage commitment or progression of CD4(+) T cells. We also found that Ptprk appears to function in parallel with or downstream of Th-POK/cKrox (also known as ZBTB7B), a master regulator of T cell lineage decision.

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Unresponsiveness of CD4⁻8^+/− thymocytes to lectin stimulation in LEC mutant rats

Cited by 5 publications

References 35 publications

A Novel Gene Essential for the Development of Single Positive Thymocytes

A Novel Gene Essential for the Development of Single Positive Thymocytes

Development of Inflammatory Bowel Disease in Long-Evans Cinnamon Rats Based on CD4+CD25+Foxp3+ Regulatory T Cell Dysfunction

Maturational arrest of thymocyte development is caused by a deletion in the receptor-like protein tyrosine phosphatase κ gene in LEC rats

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Unresponsiveness of CD4−8+/− thymocytes to lectin stimulation in LEC mutant rats

Cited by 5 publications

References 35 publications

A Novel Gene Essential for the Development of Single Positive Thymocytes

A Novel Gene Essential for the Development of Single Positive Thymocytes

Development of Inflammatory Bowel Disease in Long-Evans Cinnamon Rats Based on CD4+CD25+Foxp3+ Regulatory T Cell Dysfunction

Maturational arrest of thymocyte development is caused by a deletion in the receptor-like protein tyrosine phosphatase κ gene in LEC rats

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Unresponsiveness of CD4⁻8^+/− thymocytes to lectin stimulation in LEC mutant rats