Human Cytomegalovirus (HCMV) US2 Protein Interacts with Human CD1d (hCD1d) and Down-Regulates Invariant NKT (iNKT) Cell Activity

Han, Ji‐Hye; Rho, Seung Bae; Lee, Jae Yeon; Bae, Joonbeom; Park, Seho; Lee, Suk Jun; Lee, Sang Yeol; Ahn, Curie; Kim, Jae Young; Chun, Taehoon

doi:10.1007/s10059-013-0221-8

Cited by 15 publications

(8 citation statements)

References 45 publications

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“…As a result of coevolution, most, if not all, herpesviruses have developed intricate mechanisms by which to modulate host immune systems for the benefit of viral survival (6). 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).…”

mentioning

confidence: 99%

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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mentioning

confidence: 99%

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

Xiong

Rao

Kim

et al. 2015

J Virol

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“…An interesting finding was the observation in PHIP of downregulation of CD1D (data not shown), a nonclassical HLA class I molecule that recognizes NKT cell TCR. HCMV has been shown to downregulate CD1d at the transcriptional level, thereby acting as an immune escape mechanism (45). This extensive study shows that during the symptomatic stage of acute HCMV infection, PHIP mounted appropriate cellular immune responses.…”

Section: Discussionmentioning

confidence: 83%

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

Riou

Bressollette-Bodin

Boutoille³

et al. 2017

J Virol

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Primary human cytomegalovirus (HCMV) infection usually goes unnoticed, causing mild or no symptoms in immunocompetent individuals. However, some rare severe clinical cases have been reported without investigation of host immune responses or viral virulence. In the present study, we investigate for the first time phenotypic and functional features, together with gene expression profiles in immunocompetent adults experiencing a severe primary HCMV infection. Twenty primary HCMV-infected patients (PHIP) were enrolled, as well as 26 HCMVseronegative and 39 HCMV-seropositive healthy controls. PHIP had extensive lymphocytosis marked by massive expansion of natural killer (NK) and T cell compartments. Interestingly, PHIP mounted efficient innate and adaptive immune responses with a deep HCMV imprint, revealed mainly by the expansion of NKG2C ϩ NK cells, CD16 ϩ V␦2(Ϫ) ␥␦ T cells, and conventional HCMV-specific CD8 ϩ T cells. The main effector lymphocytes were activated and displayed an early immune phenotype that developed toward a more mature differentiated status. We suggest that both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage observed in PHIP. Taken together, these findings bring new insights into the comprehensive understanding of immune mechanisms involved during primary HCMV infection in immunocompetent individuals.IMPORTANCE HCMV-specific immune responses have been extensively documented in immunocompromised patients and during in utero acquisition. While it usually goes unnoticed, some rare severe clinical cases of primary HCMV infection have been reported in immunocompetent patients. However, host immune responses or HCMV virulence in these patients has not so far been investigated. In the present study, we show massive expansion of NK and T cell compartments during the symptomatic stage of acute HCMV infection. The patients mounted efficient innate and adaptive immune responses with a deep HCMV imprint. The massive lymphocytosis could be the result of nonadapted or uncontrolled immune responses limiting the effectiveness of the specific responses mounted. Both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage. Furthermore, we cannot exclude a delayed immune response caused by immune escape established by HCMV strains.

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“…US2 and US11 induce rapid translocation of MHC class I heavy chains from the ER into the cytosol and subsequent degradation by the proteasome ( 271 , 272 ). US2 and US11 also physically interact with CD1d but do not downregulate CD1d surface expression ( 273 , 274 ). However, reduced activation of iNKT cells after stimulation with αGalCer-pulsed US2-expressing APCs has been reported but the underlying mechanism is unclear ( 274 ).…”

Section: Viral Evasion Of Cd1-restricted T Cellsmentioning

confidence: 99%

CD1-Restricted T Cells During Persistent Virus Infections: “Sympathy for the Devil”

Schönrich

Raftery

2018

Front. Immunol.

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Some of the clinically most important viruses persist in the human host after acute infection. In this situation, the host immune system and the viral pathogen attempt to establish an equilibrium. At best, overt disease is avoided. This attempt may fail, however, resulting in eventual loss of viral control or inadequate immune regulation. Consequently, direct virus-induced tissue damage or immunopathology may occur. The cluster of differentiation 1 (CD1) family of non-classical major histocompatibility complex class I molecules are known to present hydrophobic, primarily lipid antigens. There is ample evidence that both CD1-dependent and CD1-independent mechanisms activate CD1-restricted T cells during persistent virus infections. Sophisticated viral mechanisms subvert these immune responses and help the pathogens to avoid clearance from the host organism. CD1-restricted T cells are not only crucial for the antiviral host defense but may also contribute to tissue damage. This review highlights the two edged role of CD1-restricted T cells in persistent virus infections and summarizes the viral immune evasion mechanisms that target these fascinating immune cells.

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Human Cytomegalovirus (HCMV) US2 Protein Interacts with Human CD1d (hCD1d) and Down-Regulates Invariant NKT (iNKT) Cell Activity

Cited by 15 publications

References 45 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

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

CD1-Restricted T Cells During Persistent Virus Infections: “Sympathy for the Devil”

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