Proliferative T Cell Responses to Four Human Cytomegalovirus-Specific Proteins in Healthy Subjects and Solid Organ Transplant Recipients

Zanten, Jacoba van; Harmsen, Martin C.; Meer, Piet Van Der; Bij, W. van der; Son, W. J. van; Giessen, M. van der; Prop, Jochum; Leij, Lfmh de

doi:10.1093/infdis/172.3.879

Cited by 34 publications

(14 citation statements)

References 11 publications

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“…[9][10][11][12] Although pp65 is known to both induce a strong humoral 35 and cellular immune response during natural infection, [36][37][38][39] we here show that the pp65 protein does also enable virus-infected cells to escape immune recognition. The function of this process for viral replication is presently unknown.…”

Section: Discussionmentioning

confidence: 64%

Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR α-chain

Odeberg

Plachter²,

Brandén³

et al. 2003

Blood

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Human cytomegalovirus (HCMV) has developed multiple strategies to escape immune recognition. Here, we demonstrate that HCMV down-regulates HLA-DR expression in infected interferon ␥ (IFN-␥)-stimulated fibroblasts at 1 day after infection. Decreased HLA-DR expression was not observed on cells infected with an HCMV strain lacking the pp65 gene IntroductionHuman cytomegalovirus (HCMV) belongs to the ␤ herpes family, and a primary infection is followed by latency and/or a persistent infection. 1 Although HCMV infection is usually asymptomatic in healthy individuals, the virus can cause severe morbidity and mortality in immunocompromised patients, eg, patients who have received a transplant and patients with AIDS. T cells play an important role in combating intracellular pathogens. Activation of T cells depends on their ability to recognize foreign peptides associated with either HLA class I (cytotoxic T cells, CTL) or HLA class II molecules (CD4 ϩ T cell). Although HLA class I molecules are expressed by all nucleated cells, HLA class II molecules are present only on antigen-presenting cells, such as dendritic cells, macrophages, and B cells. However, HLA class II expression can be induced on other cells by, for example, interferon ␥ (IFN-␥) stimulation. Both the inducible and the constitutive HLA class II expression is tightly regulated, and multiple proteins are involved in this process. 2 Increased or induced HLA class II expression by IFN-␥ 3 is mediated through activation of the Jak/Stat signaling pathway and transcription of the class II transactivator (CIITA), 4 which initiates HLA class II transcription. Furthermore, several proteins are responsible for controlling the transportation and peptide loading of HLA class II molecules. Three important proteins in this process are HLA-DM, the invariant chain (Ii), and the class II-associated invariant chain peptide (CLIP). Although the invariant chain is involved in the correct folding of the HLA class II complex in the endoplasmic reticulum (ER) and transportation of the complex to the class II compartment (MIIC), prevention of peptide binding in the ER is mediated by CLIP. HLA-DM catalyses the release of CLIP, and the binding of antigenic peptides to the cleft in the HLA class II molecules present in the MIIC. 5 CD4 ϩ T cells play a key role in the early activation of CTL as well as in B-cell activation. HCMV immediately early (IE)-specific CD4 ϩ T cells have been shown to produce cytokines, which inhibit HCMV replication in U373 MG cells, 6 and CD4 ϩ T cells can also control and clear murine CMV (MCMV) infection. 7,8 Thus, immune evasion strategies affecting HLA class II expression and antigen presentation to CD4 ϩ T cells would be of utmost importance for the virus to avoid early immune recognition. Although several different HCMV proteins 9-13 that interfere with HLA class I expression have been identified, the mechanisms and the viral proteins involved in down-regulation of HLA class II molecules on HCMV-infected cells are less characterized. Several studies ...

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Section: Discussionmentioning

confidence: 64%

Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR α-chain

Odeberg

Plachter²,

Brandén³

et al. 2003

Blood

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“…Nevertheless, in latently infected recipients, as might be the case for most allografts, viral replication is not required, and increased expression of genes involved in inflammation and fibrosis was observed (90). Anti-CMV immune responses have been demonstrated against latently infected ECs and serve to augment chronic inflammation in grafts undergoing allogenic immune responses; viral reactivation and inflammation are mediated in part by tumor necrosis factor a (TNF-a) released by activated NF-kB cells and in most febrile responses (91,92). TNF has been shown to stimulate the activity of the CMV immediate-early protein (IE) enhancer/promoter region in human monocytic cells and to drive CMV reactivation (93).…”

Section: Viral Genetics and Variability In Immune Responsementioning

confidence: 99%

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Kaminski

Fishman

2016

American Journal of Transplantation

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Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and cd T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.

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“…Each 25-L PCR reaction contained 1 ϫ PCR buffer II, 2 mM MgCl 2 , 0.8 mM dNTP, 0.5 L target complementary DNA (cDNA), 0.625 U AmpliTaq Gold DNA polymerase, one of 23 forward primers specific for the TCR V␤ 1, 2, 3, 4, 5.1, 5. 2,6,7,8,9,11,12,13,14,15,16,17,18,20,21,22,23, and 24 genes (each at a concentration of 1 M), and a common constant region-specific reverse primer labeled at its 5Ј end with a 6-FAM moiety (also at a concentration of 1 M). All primers were supplied by Life Technologies.…”

Section: V␤ Spectratypingmentioning

confidence: 99%

“…As a source of antigen we used the immunodominant HLA-A*0201-restricted CMV pp65 matrix protein peptide, pp65 [495][496][497][498][499][500][501][502][503] . Pp65 is recognized by more than 70% of CMV-specific CTLs, 12,[20][21][22][23][24] and the HLA-A*0201 phenotype occurs at high frequency in all ethnic groups. [15][16][17][18][19] Because pp65 is processed and presented before endogenous viral replication, pp65-specific CTLs may preempt CMV spread.…”

Section: Introductionmentioning

confidence: 99%

Isolation and expansion of cytomegalovirus-specific cytotoxic T lymphocytes to clinical scale from a single blood draw using dendritic cells and HLA-tetramers

Szmania

Galloway

Bruorton

et al. 2001

Blood

125

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Cytomegalovirus (CMV) reactivation in immunocompromised recipients of allogeneic stem cell transplantation is a cause of morbidity and mortality from viral pneumonitis. Antiviral drugs given to reactivating patients have reduced the mortality from CMV but have toxic side effects and do not always prevent late CMV disease. Cellular immunotherapy to prevent CMV disease is less toxic and could provide prolonged protection. However, a practical approach to generating sufficient quantities of CMV-specific cytotoxic T cells (CTLs) is required. This study describes a system for generating sufficient CMV-specific CTLs for adoptive immuno-

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Proliferative T Cell Responses to Four Human Cytomegalovirus-Specific Proteins in Healthy Subjects and Solid Organ Transplant Recipients

Cited by 34 publications

References 11 publications

Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR α-chain

Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR α-chain

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Isolation and expansion of cytomegalovirus-specific cytotoxic T lymphocytes to clinical scale from a single blood draw using dendritic cells and HLA-tetramers

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