T cell receptor-dependent activation of human lymphocytes through cell surface ganglioside GT1b: implications for innate immunity

ABSTRACT We have performed a screen aimed at identifying human herpesvirus 6 (HHV-6)-encoded proteins that modulate immune recognition. Here we show that the U24 protein encoded by HHV-6 variant A downregulates cell surface expression of the T-cell receptor (TCR)/CD3 complex, a complex essential to T-cell activation and the generation of an immune adaptive response. In the presence of U24, the TCR/CD3 complex is endocytosed but is not recycled back to the plasma membrane. Instead, it accumulates in early and late endosomes. Interestingly, whereas CD3 downregulation from the cell surface is normally associated with T-cell activation, U24 downregulates CD3 independently of T-cell activation. Moreover, we found that U24-expressing T cells are resistant to activation by antigen-presenting cells. HHV-6 has evolved a unique mechanism of inhibition of T-cell activation that may impair the establishment of an adaptive immune response. Furthermore, lymphocyte activation creates an environment favorable to the reactivation and replication of lymphotropic herpesviruses. Thus, by inhibiting T-cell activation, HHV-6 might limit its reactivation and thus minimize immune recognition.

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Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy

Science Translational Medicine ◽

10.1126/scitranslmed.aaz6667 ◽

2020 ◽

Vol 12 (571) ◽

pp. eaaz6667

Author(s):

Meixi Hao ◽

Siyuan Hou ◽

Weishuo Li ◽

Kaiming Li ◽

Lingjing Xue ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Surface ◽

Cell Therapy ◽

Solid Tumors ◽

T Cell Receptor ◽

Chimeric Antigen Receptor ◽

Cell Receptor ◽

T Cell Therapy ◽

Engineered T Cells

Treatment of solid tumors with T cell therapy has yielded limited therapeutic benefits to date. Although T cell therapy in combination with proinflammatory cytokines or immune checkpoints inhibitors has demonstrated preclinical and clinical successes in a subset of solid tumors, unsatisfactory results and severe toxicities necessitate the development of effective and safe combinatorial strategies. Here, the liposomal avasimibe (a metabolism-modulating drug) was clicked onto the T cell surface by lipid insertion without disturbing the physiological functions of the T cell. Avasimibe could be restrained on the T cell surface during circulation and extravasation and locally released to increase the concentration of cholesterol in the T cell membrane, which induced rapid T cell receptor clustering and sustained T cell activation. Treatment with surface anchor-engineered T cells, including mouse T cell receptor transgenic CD8+ T cells or human chimeric antigen receptor T cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma. Glioblastoma was completely eradicated in three of the five mice receiving surface anchor-engineered chimeric antigen receptor T cells, whereas mice in other treatment groups survived no more than 64 days. Moreover, the administration of engineered T cells showed no obvious systemic side effects. These cell-surface anchor-engineered T cells hold translational potential because of their simple generation and their safety profile.

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A New Marker on Chicken Hematopoietic Cells is Defined by a Monoclonal Antibody Raised Against a VßChain of the Human TCR

Developmental Immunology ◽

10.1155/1992/38159 ◽

1992 ◽

Vol 2 (4) ◽

pp. 273-284

Author(s):

Anne-Sophie Lacoste-Eleaume ◽

Christian Bleux ◽

Catherine Corbel ◽

Dominique Carriere ◽

Philippe Poncelet ◽

...

Keyword(s):

Molecular Weight ◽

Monoclonal Antibody ◽

T Cell ◽

Cell Surface ◽

Cell Line ◽

T Cell Receptor ◽

Hematopoietic Cells ◽

Apparent Molecular Weight ◽

Cell Receptor ◽

Cell Lysates

In this paper, we show that a mouse monoclonal antibody, 111-427, specific for the Vß5.3 chain of the human T-cell receptor (TCR) for antigen, also reacts with chicken hematopoietic cells. Our data indicate that the majority of 111-427 positive cells among peripheral blood leucocytes (PBL) are thrombocytes. This antibody also recognizes two in vitro cell lines, III-C5, an IL-2-dependent T-cell-line and HD11, a macrophage cell line. In addition, erythrocytes and a minor subpopulation of thymus and spleen cells are also stained by the monoclonal antibody (mAb). No specific immunoprecipitation could be detected from125I radiolabeled cell lysates. By Western blotting techniques, the 111- 427 mAb identifies a single band of apparent molecular weight 91 kD, unaffected by reduction, from III-C5 and HD11 cell lysates. This band is absent in negative cell control lysates. On thrombocytes, the apparent molecular weight of the band is shifted to 87 kD. These results indicate that the mAb does not recognize the chicken T-cell receptor for antigen, but a cell surface marker shared primarily between thrombocytes and erythrocytes. This new chicken cell marker is compared to other cell surface markers in avian or mammalian species that present some analogies in their tissue distribution.

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Wild type and tailless CD8 display similar interaction with microfilaments during capping

Journal of Cell Science ◽

10.1242/jcs.100.2.329 ◽

1991 ◽

Vol 100 (2) ◽

pp. 329-337

Author(s):

P. Andre ◽

J. Gabert ◽

A.M. Benoliel ◽

C. Capo ◽

C. Boyer ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

T Cell ◽

Cell Surface ◽

T Cell Receptor ◽

Cell Receptor ◽

Class I ◽

Surface Markers ◽

Major Histocompatibility ◽

Wild Type ◽

Histocompatibility Complex

We examined the influence of the intracytoplasmic region of CD8 alpha on capping and interaction with microfilaments. We used cell clones obtained by transfecting a CD4+ T-cell hybridoma with (a) T-cell receptor (TCR) alpha and beta chains from a cytolytic clone and (b) CD8 alpha genes that were either native or modified by extensive deletion of the intracytoplasmic region or replacement of the transmembrane and intracytoplasmic domains with those of a class I major histocompatibility complex gene (Letourneur et al. (1990). Proc. natn. Acad. Sci. U.S.A. 87, 2339–2343). Different cell surface structures were cross-linked with anti-T-cell receptor, anti-CD8 or anti-class I monoclonal antibodies and anti-immunoglobulin (Fab')2. Double labeling and quantitative image analysis were combined to monitor fluorescence anisotropy and correlation between different markers. Microfilaments displayed maximal polarization within two minutes. The correlation between these structures and surface markers was then maximal and started decreasing, whereas the redistribution of surface markers remained stable or continued. Furthermore, wild type and altered CD8 alpha exhibited similar ability to be capped and to induce co-capping of TCR and MHC (major histocompatibility complex) class I: the fraction of cell surface label redistributed into a localized cap ranged between 40% and 80%. Finally, cytochalasin D dramatically decreased CD8 capping in all tested clones. It is concluded that the transmembrane and/or intracellular domains of CD8 molecules are able to drive the extensive redistributions of membrane structures and cytoskeletal elements that are triggered by CD8 cross-linking.

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