Inhibition of TCR Signaling by Herpes Simplex Virus

Sloan, Derek D.; Han, Jin Young; Sandifer, T.; Stewart, M. Kathryn; Hinz, Aaron; Yoon, Miri; Johnson, David C.; Spear, Patricia G.; Jerome, Keith R.

doi:10.4049/jimmunol.176.3.1825

Cited by 49 publications

(67 citation statements)

References 72 publications

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“…These proteins include the Epstein-Barr virus LMP1 protein (23), human immunodeficiency virus type 1 Nef (58), measles virus proteins (3), the human herpesvirus 8 K5 protein (11), and herpes simplex virus and herpesvirus saimiri (9,47).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12 ^I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1

Fukumoto

Dundr

Nicot

et al. 2007

J Virol

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The p12I protein of human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is a small oncoprotein that increases calcium release following protein kinase C activation by phorbol myristate acetate, and importantly, this effect is linker for activation of T cells (LAT) independent. Here, we demonstrate that p12 I inhibits the phosphorylation of LAT, Vav, and phospholipase C-␥1 and decreases NFAT (nuclear factor of activated T cells) activation upon engagement of the T-cell receptor (TCR) with anti-CD3 antibody. Furthermore, we demonstrate that p12 I localizes to membrane lipid rafts and, upon engagement of the TCR, relocalizes to the interface between T cells and antigen-presenting cells, defined as the immunological synapse. A p12 I knockout molecular clone of HTLV-1 expresses more virus upon antigen stimulation than the isogenic wild type, suggesting that, by decreasing T-cell responsiveness, p12I curtails viral expression. Thus, p12 I has contrasting effects on TCR signaling: it down-regulates TCR in a LAT-dependent manner on one hand, and on the other, it increases calcium release in a LAT-independent manner. The negative regulation of T-cell activation by p12 I may have evolved to minimize immune recognition of infected CD4 ؉ T cells, to impair the function of infected cytotoxic CD8 ؉ T cells, and to favor viral persistence in the infected host.Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) causes a rare, aggressive hematopoietic malignancy of mature T cells, designated adult T-cell leukemia/lymphoma, as well as a progressive myelopathy defined as HTLV-1-associated myelopathy/tropical spastic paraparesis (18,20,25,42,55). HTLV-1 infects human CD4 ϩ and CD8 ϩ (22,33,35,39,43) T cells of memory phenotype and is believed to confer a proliferative and survival advantage on infected memory T-cell clones, with consequent accumulation of somatic mutations and neoplastic transformation (16). The provirus is thought to be mostly latent, mainly in resting T cells (21). However, once T cells are stimulated by antigen, the proviral DNA can be expressed, endangering the survival of the infected cells because of immune recognition.The HTLV-1 genome, in addition to structural (Gag and Env) and enzymatic (Pol) proteins, encodes positive regulators of viral expression from open reading frames (ORFs) III and IV, such as Tax and Rex, as well as two negative regulators, p30 II (ORF II) (40) and HBZ, which is encoded from the minus strand RNA (19). ORF I encodes a 12-kDa protein (p12 I ) that in cells is localized in the endoplasmic reticulum (ER)/Golgi (13,28,32). The p12 I protein has been shown to have multiple functions. p12 I interacts with the interleukin-2 receptor (IL-2R) ␤ and ␥ c chains, increases STAT-5 activation, and decreases the threshold of the IL-2 requirement for T-cell proliferation (38, 41) in primary human lymphocytes. In the ER/Golgi, p12 I binds both the IL-2 receptor chains and the major histocompatibility complex (MHC) class I heavy chain and interferes with their trafficking to the cell surface (28, ...

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Section: Discussionmentioning

confidence: 99%

Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12 ^I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1

Fukumoto

Dundr

Nicot

et al. 2007

J Virol

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“…Despite the well-established role of Lck in initiating signaling through the T cell receptor (TCR) (reviewed in reference 56), VP11/12-dependent activation of Lck does not trigger TCR signaling (72). Indeed, HSV-1 infection inhibits TCR signaling (53), and VP11/12 is not required for this effect (72). Thus, the biological function of Lck-dependent tyrosine phosphorylation of VP11/12 has yet to be defined.…”

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confidence: 99%

Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Wagner

Smiley

2011

J Virol

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We previously showed that the herpes simplex virus 1 (HSV-1) tegument protein VP11/12 activates the lymphocyte-specific Src family kinase (SFK) Lck and is tyrosine phosphorylated in an Lck-dependent manner during T cell infection. We now extend these findings to show that ectopic expression of Lck induces robust tyrosine phosphorylation of VP11/12 in Vero cells, strongly suggesting that VP11/12 participates in an Lckmediated signaling pathway as a substrate of Lck or a kinase activated by Lck. We sought to elucidate signaling events downstream of VP11/12-SFK interactions. SFKs lie upstream of the canonical phosphoinositide 3-kinase (PI3K)-Akt pathway in signaling emanating from immune receptors, growth factor receptors, and polyomavirus middle T antigen. Here, we show that VP11/12 is required for virus-induced activation of PI3K-Akt signaling in HSV-infected Jurkat T cells and primary fibroblasts. VP11/12 interacts with PI3K or PI3K signaling complexes during infection, suggesting that VP11/12 activates PI3K directly. SFK activity is required for tyrosine phosphorylation of VP11/12, VP11/12-PI3K interactions, and Akt activation in infected fibroblasts, suggesting that SFK-dependent phosphorylation of VP11/12 is required for interactions with downstream signaling effectors. Akt controls many biological functions, including cell survival, cell motility, and translation, but it is currently unclear which Akt targets are modulated by VP11/12 during infection. Although the Akt target mTORC1 is activated during HSV-1 infection, VP11/12 is not required for this effect, implying that one or more additional viral proteins regulate this pathway. Further studies are therefore required to determine which Akt targets and associated biological functions are uniquely modulated by VP11/12.

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“…Inhibition of transporter associated with antigen presentation (TAP), downregulation of HLA class I (28,29), decreased DC co-stimulation (30), and disruption of TCR signaling (31,32) mediated by various HSV genes all likely contribute to difficulties with direct presentation in in vitro settings. In contrast, murine HSV data show that both the priming of naive CD8 responses and the recall of memory CD8 + cells use cross-rather than direct priming and presentation (33)(34)(35)(36)(37)(38).…”

Section: Introductionmentioning

confidence: 99%

Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

Jing¹,

Haas²,

Chong³

et al. 2012

J. Clin. Invest.

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Herpes simplex virus type 1 (HSV-1) not only causes painful recurrent oral-labial infections, it can also cause permanent brain damage and blindness. There is currently no HSV-1 vaccine. An effective vaccine must stimulate coordinated T cell responses, but the large size of the genome and the low frequency of HSV-1-specific T cells have hampered the search for the most effective T cell antigens for inclusion in a candidate vaccine. We have now developed what we believe to be novel methods to efficiently generate a genome-wide map of the responsiveness of HSV-1-specific T cells, and demonstrate the applicability of these methods to a second complex microbe, vaccinia virus. We used cross-presentation and CD137 activation-based FACS to enrich for polyclonal CD8 + T effector T cells. The HSV-1 proteome was prepared in a flexible format for analyzing both CD8 + and CD4 + T cells from study participants. Scans with participant-specific panels of artificial APCs identified an oligospecific response in each individual. Parallel CD137-based CD4 + T cell research showed discrete oligospecific recognition of HSV-1 antigens. Unexpectedly, the two HSV-1 proteins not previously considered as vaccine candidates elicited both CD8 + and CD4 + T cell responses in most HSV-1-infected individuals. In this era of microbial genomics, our methods -also demonstrated in principle for vaccinia virus for both CD8 + and CD4 + T cells -should be broadly applicable to the selection of T cell antigens for inclusion in candidate vaccines for many pathogens. IntroductionHerpes simplex virus type 1 (HSV-1) infects 60% of the US population and has a significant cumulative health care burden in addition to causing painful recurrent oral-labial infections. For example, brain and eye infections can cause permanent damage or blindness (1). HSV-1 also causes approximately 50% of clinical first-episode genital herpes in the United States. Vaccines for HSV that have been tested thus far have failed in clinical trials, including a recent phase III trial of an adjuvanted glycoprotein D (gD2) product (2). This vaccine elicits antibody and CD4 + T cell responses but fails to induce CD8 responses. Newer platforms can elicit CD8 + and CD4 + cells, but they require rationally selected T cell antigens. We therefore developed methods to permit measurement of both CD8 and CD4 responses to the complete HSV-1 proteome to begin rational prioritization of next-generation vaccine candidates.Several recent observations support the concept that an effective HSV vaccine will need to induce coordinated CD8 + and CD4 + T cell responses. HSV-1-specific CD8 + T cells localize to the site of HSV-1 infection in human and murine trigeminal ganglia (TG) (3-5), and both HSV-specific CD8 + and CD4 + T cells localize to acute and healed sites of skin infection in mice and humans, sug-

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Inhibition of TCR Signaling by Herpes Simplex Virus

Cited by 49 publications

References 72 publications

Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12 ^I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1

Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12 ^I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1

Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

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Inhibition of TCR Signaling by Herpes Simplex Virus

Cited by 49 publications

References 72 publications

Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12 I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1

Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12 I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1

Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

Contact Info

Product

Resources

About

Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12 ^I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1

Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12 ^I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1