Generation of NK1.1<sup>+</sup>T cell antigen receptor α/β<sup>+</sup>thymocytes associated with intact thymic structure

Nakagawa, Kenta; Iwabuchi, Kazuya; Ogasawara, Kunio; Ato, Manabu; Kajiwara, Meisetsu; Nishihori, H.; Iwabuchi, Chikako; Ishikura, Hiroshi; Good, Robert A.; Onoé, Kazunori

doi:10.1073/pnas.94.6.2472

Cited by 37 publications

(31 citation statements)

References 34 publications

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“…Thymic structure is disorganized in aly mice; the boundary of cortex and medulla is unclear (9,10), and ER-TR5-positive cells (medullary epithelial cells) are sparse (43). We also found that epithelial cells that bind the lectin UEA-1 (UEA-1 ϩ medullary epithelial cells) (44) were absent from the thymus of aly mice (our unpublished observation).…”

Section: Discussionmentioning

confidence: 66%

Essential Role of NF-κB-Inducing Kinase in T Cell Activation Through the TCR/CD3 Pathway

Matsumoto

Yamada

Yoshinaga

et al. 2002

The Journal of Immunology

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NF-κB-inducing kinase (NIK) is involved in lymphoid organogenesis in mice through lymphotoxin-β receptor signaling. To clarify the roles of NIK in T cell activation through TCR/CD3 and costimulation pathways, we have studied the function of T cells from aly mice, a strain with mutant NIK. NIK mutant T cells showed impaired proliferation and IL-2 production in response to anti-CD3 stimulation, and these effects were caused by impaired NF-κB activity in both mature and immature T cells; the impaired NF-κB activity in mature T cells was also associated with the failure of maintenance of activated NF-κB. In contrast, responses to costimulatory signals were largely retained in aly mice, suggesting that NIK is not uniquely coupled to the costimulatory pathways. When NIK mutant T cells were stimulated in the presence of a protein kinase C (PKC) inhibitor, proliferative responses were abrogated more severely than in control mice, suggesting that both NIK and PKC control T cell activation in a cooperative manner. We also demonstrated that NIK and PKC are involved in distinct NF-κB activation pathways downstream of TCR/CD3. These results suggest critical roles for NIK in setting the threshold for T cell activation, and partly account for the immunodeficiency in aly mice.

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Section: Discussionmentioning

confidence: 66%

Essential Role of NF-κB-Inducing Kinase in T Cell Activation Through the TCR/CD3 Pathway

Matsumoto

Yamada

Yoshinaga

et al. 2002

The Journal of Immunology

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“…Indeed, it has been shown that the NK1.1 ϩ ␣͞␤TCR ϩ thymocytes are not positively selected under the influence of thymic epithelial cells but are generated in the presence of CD4 ϩ 8 ϩ double positive thymocytes, which express nonpolymorphic major histocompatibility complex class I-like molecules, CD1 (2,(6)(7)(8)(9). This is so even though we recently have found that an intact microenvironment of the thymus makes up a component that is also important in generation of the NK1.1 ϩ ␣͞␤TCR ϩ thymocytes (10). In addition, Taniguchi et al (11) and Bendelac et al (12) reported that expression of an invariant TCR ␣ chain, V␣14-J␣281, is an essential requirement for development of (13,14).…”

Section: T Cells Of the I-mentioning

confidence: 81%

Intrathymic selection of NK1.1⁺α/β T cell antigen receptor (TCR)⁺cells in transgenic mice bearing TCR specific for chicken ovalbumin and restricted to I-A^d

Iwabuchi

Nakagawa

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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A BSTR ACTGeneration and negative selection of NK1.1 ؉ ␣͞␤ T cell receptor (TCR) ؉ thymocytes were analyzed using TCR-transgenic (B10.D2 ؋ DO10)F 1 and (C57BL͞6 ؋ DO10)F 1 mice and Rag-1 ؊͞؊ ͞DO10 mice, which had been established by breeding and backcrossing between Rag-1 ؊͞؊ and DO10 mice. Almost all T cells from these mice were shown to bear V␣13͞V␤8.2 that is specific for chicken ovalbumin (cOVA) and restricted to I-A d . A normal proportion of the NK1.1 ؉ V␣13͞V␤8.2 ؉ thymocytes was generated in these mice. However, the actual cell number of both NK1.1 ؉ and NK1.1 ؊ thymocytes in I-A d͞d mice (positive selecting background) was larger than that in I-A b͞d mice (negative selecting background). Markedly low but significant proportions of NK1.1 ؉ V␣13͞V␤8.2 ؉ cells were detected in the spleens from I-A d͞d and I-A b͞d mice. It was shown that the splenic NK1.1 ؉

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“…We and others have demonstrated that this is due to defective NF-B activation through the lymphotoxin (LT)-␤ receptor (LT␤R) (6,7,9), a receptor essential for the development of lymphoid organs (10). Thymic structure is also disorganized in NIK aly/aly mice, which is not observed in mice deficient for LT-␣ or LT-␤ (10); the medulla in NIK aly/aly mice is smaller than that in NIK aly/ϩ mice, and the boundary of the cortex and medulla is unclear (5,6,11). In addition to this abnormal lymphoid organogenesis, NIK aly/aly mice also serve as a model of autoimmune disease, but of unknown etiology (12); histopathological analysis of NIK aly/aly mice has revealed chronic inflammatory changes in several organs, including the liver, pancreas, lung, salivary gland, and lacrimal gland (Refs.…”

Section: Nf-b-inducing Kinase Establishes Self-tolerance In a Thymicmentioning

confidence: 99%

NF-κB-Inducing Kinase Establishes Self-Tolerance in a Thymic Stroma-Dependent Manner

Kajiura¹,

Sun²,

Nomura

et al. 2004

The Journal of Immunology

198

225

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Physical contact between thymocytes and the thymic stroma is essential for T cell maturation and shapes the T cell repertoire in the periphery. Stromal elements that control these processes still remain elusive. We used a mouse strain with mutant NF-κB-inducing kinase (NIK) to examine the mechanisms underlying the breakdown of self-tolerance. This NIK-mutant strain manifests autoimmunity and disorganized thymic structure with abnormal expression of Rel proteins in the stroma. Production of immunoregulatory T cells that control autoreactive T cells was impaired in NIK-mutant mice. The autoimmune disease seen in NIK-mutant mice was reproduced in athymic nude mice by grafting embryonic thymus from NIK-mutant mice, and this was rescued by supply of exogenous immunoregulatory T cells. Impaired production of immunoregulatory T cells by thymic stroma without normal NIK was associated with altered expression of peripheral tissue-restricted Ags, suggesting an essential role of NIK in the thymic microenvironment in the establishment of central tolerance.

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Generation of NK1.1⁺T cell antigen receptor α/β⁺thymocytes associated with intact thymic structure

Cited by 37 publications

References 34 publications

Essential Role of NF-κB-Inducing Kinase in T Cell Activation Through the TCR/CD3 Pathway

Essential Role of NF-κB-Inducing Kinase in T Cell Activation Through the TCR/CD3 Pathway

Intrathymic selection of NK1.1⁺α/β T cell antigen receptor (TCR)⁺cells in transgenic mice bearing TCR specific for chicken ovalbumin and restricted to I-A^d

NF-κB-Inducing Kinase Establishes Self-Tolerance in a Thymic Stroma-Dependent Manner

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Generation of NK1.1+T cell antigen receptor α/β+thymocytes associated with intact thymic structure

Cited by 37 publications

References 34 publications

Essential Role of NF-κB-Inducing Kinase in T Cell Activation Through the TCR/CD3 Pathway

Essential Role of NF-κB-Inducing Kinase in T Cell Activation Through the TCR/CD3 Pathway

Intrathymic selection of NK1.1+α/β T cell antigen receptor (TCR)+cells in transgenic mice bearing TCR specific for chicken ovalbumin and restricted to I-Ad

NF-κB-Inducing Kinase Establishes Self-Tolerance in a Thymic Stroma-Dependent Manner

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Generation of NK1.1⁺T cell antigen receptor α/β⁺thymocytes associated with intact thymic structure

Intrathymic selection of NK1.1⁺α/β T cell antigen receptor (TCR)⁺cells in transgenic mice bearing TCR specific for chicken ovalbumin and restricted to I-A^d