Mouse Hobit is a homolog of the transcriptional repressor Blimp-1 that regulates NKT cell effector differentiation

Gisbergen, Klaas P. J. M. van; Kragten, Natasja A. M.; Hertoghs, Kirsten M. L.; Wensveen, Felix M.; Jonjić, Stipan; Hamann, Jörg; Nolte, Martijn A.; Lier, R. A. W. Van

doi:10.1038/ni.2393

Cited by 73 publications

(102 citation statements)

References 41 publications

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“…The proapoptotic phenotype could also under the control of other transcription factors in combination with PLZF, such as Hobit, which was recently shown to be involved in the terminal differentiation of iNKT cells. 33 We also found that the proapoptotic phenotype of iNKT cells is shared by MAIT cells, the second invariant T-cell lineage in humans. 7 Both populations share developmental, functional, and phenotypical features and are considered as innate-like T lymphocytes.…”

Section: Discussionmentioning

confidence: 68%

Human iNKT and MAIT cells exhibit a PLZF-dependent proapoptotic propensity that is counterbalanced by XIAP

Gérart

Sibéril

Martin

et al. 2013

Blood

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Key Points• Human innate-like lymphocytes, iNKT and MAIT cells exhibit a proapoptotic phenotype associated with increased levels of caspases.• The proapoptotic feature of iNKT and MAIT cells depends on the transcription factor PLZF and is regulated by the anti-apoptotic factor XIAP. Invariant natural killer (iNKT) T cells and mucosal-associated invariant T (MAIT) cells represent peculiar T-lymphocyte subpopulations with innate-like properties that differ from conventional T cells. iNKT are reduced in the primary immunodeficiency caused by mutations in the X-linked inhibitor of apoptosis (XIAP). By studying the mechanism of this depletion, we herein report that iNKT cells exhibit a high susceptibility to apoptosis that is not observed with conventional T cells. Elevated expression of caspases 3 and 7 accounts for the proapoptotic phenotype of iNKT cells, which is inhibited by XIAP although it exerts a moderate effect in conventional T cells. Similarly, MAIT cells exhibit a proapoptotic propensity with elevated expression of activated caspases and are decreased in XIAP-deficient individuals. Knockdown of the transcription factor PLZF/ ZBTB-16, which is involved in the effector program of iNKT cells, diminishes their proapoptotic phenotype. Conversely, overexpression of PLZF/ZBTB-16 in conventional T cells leads to a proapoptotic phenotype. Our findings identify a previously unknown pathway of regulation of innate-like T-cell homeostasis depending on XIAP and PLZF. The proapoptotic feature of iNKT cells also gives a reliable explanation of their exhaustion observed in different human IntroductionInvariant natural killer T (iNKT) lymphocytes represent a distinct T-cell lineage with innate-like traits differing from conventional T cells. 1 In humans, iNKT cells express an invariant (or semiinvariant in mice) TCR made of the V␣24/J␣18/V␤11 rearrangements, which recognize glycosphingolipids from foreign and self origin presented by the MHC class I-like monomorphic molecule CD1d. 2 Several factors required for the development of iNKT cells but not of conventional T cells have been identified including the SLAM family receptors, the SLAM-associated protein (SAP) and transcription factors, such as NF-B, Egr2, HEB, and PLZF. 3 Functionally, iNKT cells are characterized by their ability to rapidly release large amounts of T helper (Th) type 1 (Th1), Th2, and Th17 cytokines and chemokines when activated. In accordance with these unique features, many studies in mice have demonstrated their involvement in a variety of immune responses and immunopathologic conditions. 1 Recently, a second invariant T-cell subpopulation, the mucosal associated invariant T (MAIT) cells was identified both in humans and mice. [4][5][6] These cells express a semi-invariant TCR made of V␣7.2/J␣33 rearrangements and share with iNKT cells several developmental, functional, and phenotypical features. 7,8 In humans, our knowledge of the biology of iNKT cells is more limited. Indeed, iNKT cells are present in very variable albeit low proportions in con...

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Section: Discussionmentioning

confidence: 68%

Human iNKT and MAIT cells exhibit a PLZF-dependent proapoptotic propensity that is counterbalanced by XIAP

Gérart

Sibéril

Martin

et al. 2013

Blood

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“…25) Granzyme B is produced by CD8+, NK and NKT cells, and induces apoptosis in tumor cells. [26][27][28][29] The increase in granzyme B in the lymph nodes by Z-100 in the present study suggests that Z-100 may induce apoptosis of tumor cells in lymph nodes by enhancing granzyme B production.…”

Section: Discussionmentioning

confidence: 99%

Z-100, an Immunomodulatory Extract of <i>Mycobacterium tuberculosis</i> Strain Aoyama B, Prevents Spontaneous Lymphatic Metastasis of B16-BL6 Melanoma

Horii

Yoshinaga

Kobayashi

et al. 2014

Biological & Pharmaceutical Bulletin

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Lymphatic metastasis is common in advanced-stage carcinoma and is associated with a poor prognosis. However, few effective treatments to inhibit it are available. Z-100 is an immunomodulatory extract of Mycobacterium tuberculosis strain Aoyama B that contains polysaccharides such as arabinomannan and mannan. Here, we investigated the inhibitory effect of Z-100 on spontaneous lymphatic metastasis. C57BL/6N mice injected subcutaneously with B16-BL6 melanoma cells in the right hind footpad were administered Z-100 subcutaneously in the right inguinal region on a daily basis. On day twenty-one after the injection, the right inguinal lymph nodes were excised, and the extent of metastasis, the number of immune cells, and the amount of granzyme B protein in the lymph nodes were examined. We also investigated the combined effect of Z-100 and irradiation in this model. Results showed that Z-100 reduced number of animals with metastasis, with respective metastasis rates of 85.7%, 42.9%, 7.1% and 0.0% in saline, 0.1 mg/kg Z-100, 1 mg/kg Z-100 and 10 mg/kg Z-100 group. Further, mice that had been given Z-100 were found to have more immune cells and granzyme B protein in the lymph nodes than control mice. The combination of low dose Z-100 and irradiation also inhibited spontaneous lymph node metastases. These findings suggest that Z-100 may be beneficial in preventing lymphatic metastasis by enhancing the immune response.Key words lymph node metastasis; B16-BL6 melanoma cell; non-specific immunotherapy; radiation Metastasis is the main cause of death in advanced-stage cancer patients and occurs through three major routes: hematogenous, lymphogenous, and transcoelomic spread.1,2) Lymphatic metastasis in particular is common in advanced-stage carcinoma and is generally associated with a poor prognosis. Although the influence of lymphatic metastasis on prognosis is thoroughly understood, effective treatments to inhibit it remain lacking. 3,4) Lymph node dissection is frequently performed to treat or prevent (or both) lymph node metastasis in several types of cancer. These procedures are limited to early-stage cancer patients, however, and their efficacy has been questioned. 5,6) Chemotherapy and lymphangiogenesis inhibitors are administered in lieu of surgery to inhibit lymphatic metastasis, [7][8][9] but these drugs have limited efficacy due to their toxicity and poor bioavailability. Specifically, conventional chemotherapy cannot be delivered to the lymphatic system effectively without dose-limiting toxicity, requiring drug delivery systems such as a liposome-based delivery system. 9,10) Therefore, novel therapeutics are needed for the use in treating cancer patients with lymphatic metastasis.Immunotherapeutic approaches have been shown to inhibit lymphatic metastasis in animal models, indicating the potential of immunotherapy as treatment for lymphatic metastasis in humans.11-13) Z-100 is a hot-water extract of Mycobacterium tuberculosis strain Aoyama B and contains polysaccharides such as arabinomannan and mannan.14) Z-100 h...

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“…Previous reports have shown that human iNKT cells do harbor some NK-like cytolytic molecules, including granzyme and perforin (20), and a recent study has identified HOBIT (homolog of Blimp-1 in T cells, Znf683) as a transcriptional program for granzyme in mature iNKT cells that have returned back to thymus but not spleen or liver (7). Therefore, we next investigated how iNKT cells mediate the spirochete cell death and observed a Ca 2+ -dependent killing mechanism (EGTA inhibitable) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Invariant natural killer T cells act as an extravascular cytotoxic barrier for joint-invading Lyme Borrelia

Lee

Sanz

Wong

et al. 2014

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

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Significance Invariant natural killer T cells (iNKT) have been found primarily patrolling inside blood vessels in the liver, where they respond to bacterial glycolipids presented by CD1d on liver macrophages. We show joint iNKT cells are localized outside of blood vessels and respond directly to the joint-homing pathogen, Borrelia burgdorferi , which causes Lyme borreliosis using multichannel spinning-disk intravital microscopy. These iNKT cells interacted with B. burgdorferi at the vessel wall and disrupted its dissemination attempts into joints. Successful penetrance of B. burgdorferi out of the vasculature and into the joint tissue was met by a lethal attack by extravascular iNKT cells through a granzyme-dependent pathway. These results suggest a critical extravascular iNKT cell immune surveillance in joints that functions as a cytotoxic barrier.

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Mouse Hobit is a homolog of the transcriptional repressor Blimp-1 that regulates NKT cell effector differentiation

Cited by 73 publications

References 41 publications

Human iNKT and MAIT cells exhibit a PLZF-dependent proapoptotic propensity that is counterbalanced by XIAP

Human iNKT and MAIT cells exhibit a PLZF-dependent proapoptotic propensity that is counterbalanced by XIAP

Z-100, an Immunomodulatory Extract of <i>Mycobacterium tuberculosis</i> Strain Aoyama B, Prevents Spontaneous Lymphatic Metastasis of B16-BL6 Melanoma

Invariant natural killer T cells act as an extravascular cytotoxic barrier for joint-invading Lyme Borrelia

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