Expression of genes encoding cytotoxic cell-associated serine proteases in thymocytes

Held, Werner; MacDonald, H. Robson; Mueller, Christoph

doi:10.1093/intimm/2.1.57

Cited by 23 publications

(13 citation statements)

References 24 publications

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“…2B). Concordantly, CD4 SP from WT and KO mice on TCR polyclonal background showed comparable levels of mRNA of Th-POK, a master transcriptional factor for CD4 SP lineage commitment (27), whereas CD8 SP from these mice exhibited no difference in the expression of Perforin, an effector molecule specifically produced by mature CD8 cells (28) (Supplemental Fig. 2C).…”

Section: Ubc9 Is Required For T Cell Development In the Thymus And Pementioning

confidence: 79%

Ubc9 Is Required for Positive Selection and Late-Stage Maturation of Thymocytes

Wang

Ding

Demarque

et al. 2017

The Journal of Immunology

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SUMOylation is an important posttranslational modification that regulates protein function in diverse biological processes. However, its role in early T cell development has not been genetically studied. UBC9 is the only E2 enzyme for all SUMOylation. In this study, by selectively deleting Ubc9 gene in T cells, we have investigated the functional roles of SUMOylation in T cell development. Loss of Ubc9 results in a significant reduction of CD4 and CD8 single-positive lymphocytes in both thymus and periphery. Ubc9-deficient cells exhibit defective late-stage maturation post the initial positive selection with increased apoptosis and impaired proliferation, among which attenuated IL-7 signaling was correlated with the decreased survival of Ubc9-deficent CD8 single-positive cells. Furthermore, NFAT nuclear retention induced by TCR signals was regulated by SUMOylation during thymocytes development. Our study thus reveals a novel posttranslational mechanism underlying T cell development.

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Section: Ubc9 Is Required For T Cell Development In the Thymus And Pementioning

confidence: 79%

Ubc9 Is Required for Positive Selection and Late-Stage Maturation of Thymocytes

Wang

Ding

Demarque

et al. 2017

The Journal of Immunology

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“…Thymic medullary DCs are essential in the positive and negative selection of thymocytes. GrB-positive cells are present in the thymic medulla, with grB transcripts detected in double-positive (CD4 ϩ CD8 ϩ ) thymocytes (83) and in both CD4 ϩ or CD8 ϩ single-positive thymocytes (84). This suggests that thymocytes undergoing selection express grB and have cytotoxic potential.…”

Section: Cd11bmentioning

confidence: 99%

The Intracellular Granzyme B Inhibitor, Proteinase Inhibitor 9, Is Up-Regulated During Accessory Cell Maturation and Effector Cell Degranulation, and Its Overexpression Enhances CTL Potency

Hirst

Buzza

Bird

et al. 2003

The Journal of Immunology

149

151

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Granzyme B (grB) is a serine proteinase released by cytotoxic lymphocytes (CLs) to kill abnormal cells. GrB-mediated apoptotic pathways are conserved in nucleated cells; hence, CLs require mechanisms to protect against ectopic or misdirected grB. The nucleocytoplasmic serpin, proteinase inhibitor 9 (PI-9), is a potent inhibitor of grB that protects cells from grB-mediated apoptosis in model systems. Here we show that PI-9 is present in CD4+ cells, CD8+ T cells, NK cells, and at lower levels in B cells and myeloid cells. PI-9 is up-regulated in response to grB production and degranulation, and associates with grB-containing granules in activated CTLs and NK cells. Intracellular complexes of PI-9 and grB are evident in NK cells, and overexpression of PI-9 enhances CTL potency, suggesting that cytoplasmic grB, which may threaten CL viability, is rapidly inactivated by PI-9. Because dendritic cells (DCs) acquire characteristics similar to those of target cells to activate naive CD8+ T cells and therefore may also require protection against grB, we investigated the expression of PI-9 in DCs. PI-9 is evident in thymic DCs (CD3−, CD4+, CD8−, CD45+), tonsillar DCs, and DC subsets purified from peripheral blood (CD16+ monocytes and CD123+ plasmacytoid DCs). Furthermore, PI-9 is expressed in monocyte-derived DCs and is up-regulated upon TNF-α-induced maturation of monocyte-derived DCs. In conclusion, the presence and subcellular localization of PI-9 in leukocytes and DCs are consistent with a protective role against ectopic or misdirected grB during an immune response.

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“…In contrast, non-autoantigens are either not cleaved by GrB, or are cleaved by GrB at the same sites as caspases, thus generating fragments identical to those formed in other forms of apoptosis (14). In this regard, it is noteworthy that GrB is absent in mature thymocytes in the normal adult thymus (15). In order to assess the possible role of GrB in the pathogenesis of MG, we tested its ability to cleave the subunits of human AChR, and performed biochemical, immunohistochemical and molecular studies to compare GrB expression in thymus glands from MG patients with that in thymus glands from non-MG individuals.…”

Section: Introductionmentioning

confidence: 99%