A <scp>T</scp>hr/<scp>S</scp>er dual residue motif in the cytoplasmic tail of human <scp>CD</scp>1d is important for the down‐regulation of antigen presentation following a herpes simplex virus 1 infection

Liu, Jianyun; Glosson, Nicole L.; Du, Wenjun; Gervay‐Hague, Jacquelyn; Brutkiewicz, Randy R.

doi:10.1111/imm.12127

Cited by 13 publications

(25 citation statements)

References 46 publications

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“…US3 is one of the early late (␥1) genes expressed during HSV-1 infection, and its expression can be detected at approximately 3 to 4 h postinfection (8,22). Concomitant with US3 expression, the virus rapidly suppresses cell surface expression of CD1d as early as 5 to 6 h postinfection (8,10,13,14). We hypothesized that a rapid shutdown of cytoskeleton-based intracellular vesicular trafficking is a major mechanism of suppression of CD1d expression.…”

Section: Hsv-1 Protein Kinase Us3 Specifically Downregulates the Surfmentioning

confidence: 99%

“…We and other groups have demonstrated that HSV-1, upon infection, rapidly and efficiently downregulates a critical antigen-presenting molecule, CD1d, thereby inhibiting the function of NKT cells (8,10,13,14). In addition to downregulating key antigen-presenting molecules such as CD1d and MHC class I/II for the sake of immune evasion (41,42), HSV-1 reprograms the entire cellular machinery for the benefit of its own replication.…”

Section: Hsv-1 and Us3-mediated Cd1d Downregulationmentioning

confidence: 99%

“…Because of the importance of NKT cells in antiviral immunity, viruses in all three major herpesvirus families (alpha-, beta-, and gammaherpesviruses) have evolved viral mechanisms to evade CD1d and NKT cell function (7)(8)(9)(10)(11)(12). We and others have shown that herpes simplex virus 1 (HSV-1), the prototype alphaherpesvirus, has evolved to downregulate CD1d expression in antigen-presenting cells and evade NKT cell function (10,13,14). Furthermore, we have demonstrated that the viral protein kinase US3 is a major viral protein that downregulates cell surface expression of CD1d by suppressing its recycling (8).…”

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confidence: 99%

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Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression

Xiong

Rao

Kim

et al. 2015

J Virol

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Herpes simplex virus 1 (HSV-1) causes one of the most prevalent herpesviral infections in humans and is the leading etiological agent of viral encephalitis and eye infections. Our understanding of how HSV-1 interacts with the host at the cellular and organismal levels is still limited. We and others previously reported that, upon infection, HSV-1 rapidly and efficiently downregulates CD1d cell surface expression and suppresses the function of NKT cells, a group of innate T cells with critical immunoregulatory function. The viral protein kinase US3 plays a major role in this immune evasion mechanism, and its kinase activity is required for this function. In this study, we investigated the cellular substrate(s) phosphorylated by US3 and how it mediates US3 suppression of CD1d recycling. We identified the type II kinesin motor protein KIF3A as a critical kinesin factor in the cell surface expression of CD1d. Interestingly, KIF3A is phosphorylated by US3 both in vitro and in infected cells. Mass spectrometry analysis of purified KIF3A showed that it is phosphorylated predominantly at serine 687 by US3. Ablation of this phosphorylation abolished US3-mediated downregulation of CD1d expression, suggesting that phosphorylation of KIF3A is the primary mechanism of HSV-1 suppression of CD1d expression by US3 protein. Understanding of the precise mechanism of viral modulation of CD1d expression will help to develop more efficient vaccines in the future to boost host NKT cell-mediated immune responses against herpesviruses. IMPORTANCEHerpes simplex virus 1 (HSV-1) is among the most common human pathogens. Little is known regarding the exact mechanism by which this virus evades the human immune system, particularly the innate immune system. We previously reported that HSV-1 employs its protein kinase US3 to modulate the expression of the key antigen-presenting molecule CD1d to evade the antiviral function of NKT cells. Here we identified the key cellular motor protein KIF3A as a cellular substrate phosphorylated by US3, and this phosphorylation event mediates US3-induced immune evasion.

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Section: Hsv-1 Protein Kinase Us3 Specifically Downregulates the Surfmentioning

confidence: 99%

Section: Hsv-1 and Us3-mediated Cd1d Downregulationmentioning

confidence: 99%

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confidence: 99%

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Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression

Xiong

Rao

Kim

et al. 2015

J Virol

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“…Cell culture, constructs, and viral infections HEK293 cells expressing wild-type (WT) CD1d and T322A/S323A mutant have been previously described (25,26). HEK293 cells were kindly provided by Prof. Philip Cohen (MRC Protein Phosphorylation Unit, University of Dundee, Scotland, United Kingdom).…”

Section: Methodsmentioning

confidence: 99%

“…In addition, the number of NKT cells has recently been correlated with the level of HSV-1-specific antibodies in humans (34). We and others have shown that HSV-1 can inhibit CD1d-mediated antigen presentation to NKT cells by suppressing CD1d recycling (6,25,33,45). This inhibition of NKT cell function by HSV-1 is dependent on cell-to-cell contact of infected APCs and NKT cells, but not due to infection of NKT cells (6).…”

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confidence: 87%

A VP22-Null HSV-1 Is Impaired in Inhibiting CD1d-Mediated Antigen Presentation

et al. 2016

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CD1d-restricted T (natural killer T [NKT]) cells are important for controlling a herpes simplex virus (HSV) infection. One of the mechanisms of immune evasion by HSV is to downregulate CD1d-mediated activation of NKT cells. VP22 is an HSV-1-encoded protein responsible for reorganizing the host cell's cytoskeletal network and viral spreading. We have previously shown that modification of the cytoskeleton can alter CD1d-mediated antigen presentation. In this study, we found that an HSV-1 lacking VP22 (DU L 49) was impaired in its ability to inhibit CD1d-mediated antigen presentation compared with the wild-type (WT) virus; this was reversed by a repair virus (U L 49R) in CD1d-expressing cells. We further demonstrated that CD1d recycling was inhibited by infection with WT and U L 49R, but not the DU L 49 virus. Ectopic expression of VP22 in CD1d-expressing cells complemented the VP22-deficient virus in inhibiting antigen presentation. Moreover, inhibiting viral protein synthesis rescued VP22-dependent inhibition of CD1d antigen presentation. In conclusion, our findings suggest that VP22 is required (but not sufficient) for the inhibition of CD1d-mediated antigen presentation by an HSV-1 infection.

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Increased cytoplasmatic expression of cancer immune surveillance receptor CD1d in anaplastic thyroid carcinomas

et al. 2019

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Background Anaplastic thyroid carcinomas are associated with rapid tumor growth, short survival time and without any promising therapy to improve the poor prognosis. In this study, expression of immunoregulative receptor CD1d and lymphocyte infiltration in different thyroid tumors as well as in healthy tissue were analyzed in order to find new targets for an immunotherapeutic approach. Methods CD1d immunohistochemistry was performed in samples of 18 anaplastic, 17 follicular, 27 papillary, and 4 medullary thyroid carcinomas as well as in 19 specimens from normal thyroid tissue and additionally in 10 samples of sarcoma, seven malignant melanoma and three spindle‐cell lung carcinoma. Furthermore, thyroid samples were stained with antibodies against CD3, CD20, CD56, CD68, and LCA in order to analyze lymphocyte infiltration. Results For the first time CD1d receptor expression on normal thyroid tissue could be demonstrated. Moreover, anaplastic thyroid carcinomas showed significantly higher expression levels compared to other thyroid samples. Most astonishingly, CD1d expression disappeared from the cellular surface and was detected rather in the cytoplasm of anaplastic thyroid carcinoma cells. In addition, histologically similar tumors to anaplastic carcinoma like sarcoma and malignant melanoma revealed distinct CD1d staining patterns. Furthermore, infiltration of T cells, B cells, and macrophages in anaplastic thyroid carcinomas was different when compared to normal thyroid tissue and all other thyroid carcinomas. Conclusions Anaplastic thyroid carcinomas show significantly higher expression of CD1d, a receptor for NKT cells, which are subject of several anticancer therapy studies. These results may offer a novel approach to explore immunotherapeutic treatment options.

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A Thr/Ser dual residue motif in the cytoplasmic tail of human CD1d is important for the down‐regulation of antigen presentation following a herpes simplex virus 1 infection

Cited by 13 publications

References 46 publications

Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression

Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression

A VP22-Null HSV-1 Is Impaired in Inhibiting CD1d-Mediated Antigen Presentation

Increased cytoplasmatic expression of cancer immune surveillance receptor CD1d in anaplastic thyroid carcinomas

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