scholarly journals Identification of a Kd-restricted antigenic peptide encoded by murine cytomegalovirus early gene M84

2000 ◽  
Vol 81 (12) ◽  
pp. 3037-3042 ◽  
Author(s):  
Rafaela Holtappels ◽  
Doris Thomas ◽  
Matthias J. Reddehase
Keyword(s):  
Immune Evasion ◽  
Antigen Processing ◽  
Matrix Protein ◽  
Early Gene ◽  
Antigenic Peptide ◽  
Murine Cytomegalovirus ◽  
Class I Mhc ◽  
Mhc I ◽  
Cmv Matrix ◽  
Phase Protein

The two sister cytomegaloviruses (CMVs), human and murine CMV, have both evolved immune evasion functions that interfere with the major histocompatibility complex class I (MHC-I) pathway of antigen processing and presentation and are effectual in the early (E) phase of virus gene expression. However, studies on murine CMV have shown that E-phase immune evasion is leaky. An E-phase protein involved in immune evasion, namely m04-gp34, was found to simultaneously account for an antigenic peptide presented by the MHC-I molecule Dd. Recent work has demonstrated the induction of protective immunity specific for the E-phase protein M84-p65, one of two murine CMV homologues of the human CMV matrix protein UL83-pp65. In this study, the identification of the MHC-I Kd-restricted M84 peptide 297AYAGLFTPL305 is documented. This peptide is the third antigenic peptide described for murine CMV and the second that escapes immunosubversive mechanisms.

scholarly journals Expression of m157, a Murine Cytomegalovirus-Encoded Putative Major Histocompatibility Class I (MHC-I)-Like Protein, Is Independent of Viral Regulation of Host MHC-I

2006 ◽  
Vol 80 (1) ◽  
pp. 545-550 ◽  
Author(s):  
Sandeep K. Tripathy ◽  
Hamish R. C. Smith ◽  
Erika A. Holroyd ◽  
Jeanette T. Pingel ◽  
Wayne M. Yokoyama
Keyword(s):  
Antigen Processing ◽  
Cell Activation ◽  
Nk Cell ◽  
Class I ◽  
Murine Cytomegalovirus ◽  
Viral Gene ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Mhc I ◽  
Beta 2 Microglobulin

ABSTRACT A murine cytomegalovirus (MCMV)-encoded protein, m157, has a putative major histocompatibility complex class I (MHC-I) structure and is recognized by the Ly49H NK cell activation receptor. Using a monoclonal antibody against m157, in this study we directly demonstrated that m157 is a cell surface-expressed glycophosphatidylinositol-anchored protein with early viral gene kinetics. Beta-2 microglobulin and TAP1 (transporter associated with antigen processing 1) were not required for its expression. MCMV-encoded proteins that down-regulate MHC-I did not affect the expression of m157. Thus, m157 is expressed on infected cells in a manner independent of viral regulation of host MHC-I.

scholarly journals Early gene m18, a novel player in the immune response to murine cytomegalovirus

2002 ◽  
Vol 83 (2) ◽  
pp. 311-316 ◽  
Author(s):  
Rafaela Holtappels ◽  
Natascha K. A. Grzimek ◽  
Doris Thomas ◽  
Matthias J. Reddehase
Keyword(s):  
T Cell ◽  
Immune Evasion ◽  
Antigen Processing ◽  
Computational Prediction ◽  
T Cell Response ◽  
Early Gene ◽  
Murine Cytomegalovirus ◽  
Current Evidence ◽  
Antigenic Peptides ◽  
E Proteins

The identification of all antigenic peptides encoded by a pathogen, its T cell ‘immunome’, is a research aim for rational vaccine design. Screening of proteome-spanning peptide libraries or computational prediction is used to identify antigenic peptides recognized by CD8 T cells. Based on their high coding capacity, cytomegaloviruses (CMVs) could specify numerous antigenic peptides. Yet, current evidence indicates that the memory CD8 T cell response in a given haplotype is actually focused on a few viral proteins. CMVs actively interfere with antigen processing and presentation by the expression of immune evasion proteins. In the case of murine CMV (mCMV), these proteins are effectual in the early (E) phase of the virus replication cycle and should thus preclude the presentation of peptides derived from E proteins. Notably, the m18 gene is here added to a growing list of mCMV E genes that encode antigenic peptides in spite of the E phase immune evasion strategies of the virus.

scholarly journals The Putative Natural Killer Decoy Early Genem04 (gp34) of Murine Cytomegalovirus Encodes an Antigenic Peptide Recognized by Protective Antiviral CD8 T Cells

2000 ◽  
Vol 74 (4) ◽  
pp. 1871-1884 ◽  
Author(s):  
Rafaela Holtappels ◽  
Doris Thomas ◽  
Jürgen Podlech ◽  
Gernot Geginat ◽  
Hans-Peter Steffens ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Gene Product ◽  
Immune Evasion ◽  
Cd8 T Cells ◽  
Antigenic Peptide ◽  
Murine Cytomegalovirus ◽  
Mhc I

ABSTRACT Several early genes of murine cytomegalovirus (MCMV) encode proteins that mediate immune evasion by interference with the major histocompatibility complex class I (MHC-I) pathway of antigen presentation to cytolytic T lymphocytes (CTL). Specifically, the m152 gene product gp37/40 causes retention of MHC-I molecules in the endoplasmic reticulum (ER)-Golgi intermediate compartment. Lack of MHC-I on the cell surface should activate natural killer (NK) cells recognizing the “missing self.” The retention, however, is counteracted by the m04early gene product gp34, which binds to folded MHC-I molecules in the ER and directs the complex to the cell surface. It was thus speculated that gp34 might serve to silence NK cells and thereby complete the immune evasion of MCMV. In light of these current views, we provide here results demonstrating an in vivo role for gp34 in protective antiviral immunity. We have identified an antigenic nonapeptide derived from gp34 and presented by the MHC-I molecule Dd. Besides the immunodominant immediate-early nonapeptide consisting of IE1 amino acids 168-176 (IE1168-176), the early nonapeptide m04243-251 is the second antigenic peptide described for MCMV. The primary immune response to MCMV generates significant m04-specific CD8 T-cell memory. Upon adoptive transfer into immunodeficient recipients, an m04-specific CTL line controls MCMV infection with an efficacy comparable to that of an IE1-specific CTL line. Thus, gp34 is the first noted early protein of MCMV that escapes viral immune evasion mechanisms. These data document that MCMV is held in check by a redundance of protective CD8 T cells recognizing antigenic peptides in different phases of viral gene expression.

Identification of MHC-I Accessible Proteins from Salmonella Typhimurium

2001 ◽  
Vol 7 (S2) ◽  
pp. 616-617
Author(s):  
D. Ellefson ◽  
D. Parker ◽  
F. Heffron
Keyword(s):  
Salmonella Typhimurium ◽  
Host Cell ◽  
Antigen Processing ◽  
Bacterial Pathogens ◽  
Immune Surveillance ◽  
Class I ◽  
Whole Genome Analysis ◽  
Class I Mhc ◽  
Mhc I ◽  
Host Interaction

Intracellular bacterial pathogens such as Salmonella typhimurium secrete proteins into the host cell after infection. These proteins alter the normal structural and metabolic machinery of the host cell and benefit the bacterium by facilitating replication and avoidance of host immune surveillance. Since the host cytoplasmic localization of these proteins infers access to the class-I MHC antigen processing and presentation machinery of the host cell, we collectively refer to these proteins as Class- I Accessible Proteins (CAPs).The design of vaccines for new and emerging bacterial pathogens is often constrained by the selection of appropriate and specific antigens. While vaccine design is being greatly aided by whole genome analysis of bacterial pathogens, it has been of limited use in the assignment of function and host subcellular localization of a large percentage of bacterial proteins. in addition, analysis of the bacteria/host interaction is further complicated by the complex lifestyle of the pathogen.

scholarly journals Ly49R activation receptor drives self-MHC–educated NK cell immunity against cytomegalovirus infection

2019 ◽  
Vol 116 (52) ◽  
pp. 26768-26778 ◽  
Author(s):  
Awndre Gamache ◽  
John M. Cronk ◽  
William T. Nash ◽  
Patryk Puchalski ◽  
Alyssa Gillespie ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cytomegalovirus Infection ◽  
Nk Cell ◽  
Host Cells ◽  
Murine Cytomegalovirus ◽  
Virus Infections ◽  
Class I Mhc ◽  
Mhc I ◽  
Cell Immunity ◽  
Virus Immunity

Natural killer (NK) cells mediate vital control of cancer and viral infection. They rely on MHC class I (MHC I)-specific self-receptors to identify and lyse diseased cells without harming self-MHC I-bearing host cells. NK cells bearing inhibitory self-receptors for host MHC I also undergo education, referred to as licensing, which causes them to become more responsive to stimulation via activation receptor signaling. Previous work has shown that licensed NK cells selectively expand during virus infections and they are associated with improved clinical response in human patients experiencing certain chronic virus infections, including HIV and hepatitis C virus. However, the importance of inhibitory self-receptors in NK-mediated virus immunity is debated as they also limit signals in NK cells emanating from virus-specific activation receptors. Using a mouse model of MHC I-dependent (H-2Dk) virus immunity, we discovered that NK cells depend on the Ly49G2 inhibitory self-receptor to mediate virus control, which coincided with host survival during murine cytomegalovirus infection. This antiviral effect further requires active signaling in NK cells via the Ly49R activation receptor that also binds H-2Dk. In tandem, these functionally discordant Ly49 self-receptors increase NK cell proliferation and effector activity during infection, resulting in selective up-regulation of CD25 and KLRG1 in virus-specific Ly49R+Ly49G2+NK cells. Our findings establish that paired self-receptors act as major determinants of NK cell-mediated virus sensing and immunity.

scholarly journals Immune Evasion Proteins of Murine Cytomegalovirus Preferentially Affect Cell Surface Display of Recently Generated Peptide Presentation Complexes

2009 ◽  
Vol 84 (3) ◽  
pp. 1221-1236 ◽  
Author(s):  
Niels A. W. Lemmermann ◽  
Kerstin Gergely ◽  
Verena Böhm ◽  
Petra Deegen ◽  
Torsten Däubner ◽  
...  
Keyword(s):  
Cell Surface ◽  
Molecular Mechanisms ◽  
Surface Display ◽  
Cell Surface Display ◽  
Murine Cytomegalovirus ◽  
Antigenic Peptides ◽  
Mcmv Infection ◽  
Class I Mhc ◽  
Mhc I ◽  
Anchor Residue

ABSTRACT For recognition of infected cells by CD8 T cells, antigenic peptides are presented at the cell surface, bound to major histocompatibility complex class I (MHC-I) molecules. Downmodulation of cell surface MHC-I molecules is regarded as a hallmark function of cytomegalovirus-encoded immunoevasins. The molecular mechanisms by which immunoevasins interfere with the MHC-I pathway suggest, however, that this downmodulation may be secondary to an interruption of turnover replenishment and that hindrance of the vesicular transport of recently generated peptide-MHC (pMHC) complexes to the cell surface is the actual function of immunoevasins. Here we have used the model of murine cytomegalovirus (mCMV) infection to provide experimental evidence for this hypothesis. To quantitate pMHC complexes at the cell surface after infection in the presence and absence of immunoevasins, we generated the recombinant viruses mCMV-SIINFEKL and mCMV-Δm06m152-SIINFEKL, respectively, expressing the Kb-presented peptide SIINFEKL with early-phase kinetics in place of an immunodominant peptide of the viral carrier protein gp36.5/m164. The data revealed ∼10,000 Kb molecules presenting SIINFEKL in the absence of immunoevasins, which is an occupancy of ∼10% of all cell surface Kb molecules, whereas immunoevasins reduced this number to almost the detection limit. To selectively evaluate their effect on preexisting pMHC complexes, cells were exogenously loaded with SIINFEKL peptide shortly after infection with mCMV-SIINFEKA, in which endogenous presentation is prevented by an L174A mutation of the C-terminal MHC-I anchor residue. The data suggest that pMHC complexes present at the cell surface in advance of immunoevasin gene expression are downmodulated due to constitutive turnover in the absence of resupply.

scholarly journals The Proteasome Immunosubunit Multicatalytic Endopeptidase Complex-Like 1 Is a T-Cell-Intrinsic Factor Influencing Homeostatic Expansion

2007 ◽  
Vol 76 (3) ◽  
pp. 1207-1213 ◽  
Author(s):  
Dietmar M. W. Zaiss ◽  
Natascha de Graaf ◽  
Alice J. A. M. Sijts
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cell Population ◽  
Antigen Processing ◽  
Cd8 T Cell ◽  
Lymphoid Organs ◽  
T Cell Subsets ◽  
Class I Mhc ◽  
Mhc I ◽  
Deficient Mice

ABSTRACT Homeostatic regulatory mechanisms maintain the constant ratios between different lymphocyte subsets in the secondary lymphoid organs. How this dynamic equilibrium is achieved, in particular following the clonal expansion and subsequent contraction of different cells after infection, remains poorly understood. Expression of the proteasome immunosubunits has been shown to influence not only major histocompatibility complex class I (MHC-I) antigen processing and thereby T-cell responses, but also the CD4/CD8 T-cell ratios in lymphoid organs. We examined the relationships between these different immunosubunit-mediated effects in mice of various proteasome subunit compositions during infection with Listeria monocytogenes. Mice that lacked the immunosubunit multicatalytic endopeptidase complex-like 1 (MECL-1) maintained enhanced CD4/CD8 T-cell ratios during infection, while MHC-I surface levels resembled those in wild-type (wt) mice. LMP7 gene-deficient mice, on the other hand, showed reduced MHC-I expression, while their splenic CD4/CD8 ratios were similar to those in wt mice. Remarkably, analysis of bone marrow-chimeric immunosubunit gene-deficient mice, reconstituted with a mixture of wt and LMP7- plus MECL-1-deficient bone marrow, revealed that the LMP7- plus MECL-1-deficient T-cell population maintained a higher CD4/CD8 T-cell ratio than the wt T-cell population before, during, and after infection and T-cell memory formation. Since in these mice the immunosubunit-positive and immunosubunit-negative T-cell populations were selected in the same thymus and expanded in the same lymphoid environments, our findings indicate that MECL-1 influences the homeostatic equilibrium between T-cell subsets, not through indirect extracellular signals, such as MHC-I expression or the cytokine milieu, but through direct effects on T-cell-intrinsic processes.

scholarly journals Hematopoietic cell-mediated dissemination of murine cytomegalovirus is regulated by NK cells and immune evasion

2021 ◽  
Vol 17 (1) ◽  
pp. e1009255
Author(s):  
Shunchuan Zhang ◽  
Lauren E. Springer ◽  
Han-Zhi Rao ◽  
Renee G. Espinosa Trethewy ◽  
Lindsey M. Bishop ◽  
...  
Keyword(s):  
T Cells ◽  
Salivary Gland ◽  
Nk Cells ◽  
Immune Evasion ◽  
Hematopoietic Cells ◽  
Hematopoietic Cell ◽  
Murine Cytomegalovirus ◽  
Cell Mediated Immunity ◽  
Class I Mhc ◽  
Intranasal Infection

Cytomegalovirus (CMV) causes clinically important diseases in immune compromised and immune immature individuals. Based largely on work in the mouse model of murine (M)CMV, there is a consensus that myeloid cells are important for disseminating CMV from the site of infection. In theory, such dissemination should expose CMV to cell-mediated immunity and thus necessitate evasion of T cells and NK cells. However, this hypothesis remains untested. We constructed a recombinant MCMV encoding target sites for the hematopoietic specific miRNA miR-142-3p in the essential viral gene IE3. This virus disseminated poorly to the salivary gland following intranasal or footpad infections but not following intraperitoneal infection in C57BL/6 mice, demonstrating that dissemination by hematopoietic cells is essential for specific routes of infection. Remarkably, depletion of NK cells or T cells restored dissemination of this virus in C57BL/6 mice after intranasal infection, while dissemination occurred normally in BALB/c mice, which lack strong NK cell control of MCMV. These data show that cell-mediated immunity is responsible for restricting MCMV to hematopoietic cell-mediated dissemination. Infected hematopoietic cells avoided cell-mediated immunity via three immune evasion genes that modulate class I MHC and NKG2D ligands (m04, m06 and m152). MCMV lacking these 3 genes spread poorly to the salivary gland unless NK cells were depleted, but also failed to replicate persistently in either the nasal mucosa or salivary gland unless CD8+ T cells were depleted. Surprisingly, CD8+ T cells primed after intranasal infection required CD4+ T cell help to expand and become functional. Together, our data suggest that MCMV can use both hematopoietic cell-dependent and -independent means of dissemination after intranasal infection and that cell mediated immune responses restrict dissemination to infected hematopoietic cells, which are protected from NK cells during dissemination by viral immune evasion. In contrast, viral replication within mucosal tissues depends on evasion of T cells.

scholarly journals NK cells force cytomegalovirus to use hematopoietic cells and immune evasion for dissemination after mucosal infection

2019 ◽  
Author(s):  
Shunchuan Zhang ◽  
Finn Grey ◽  
Christopher M. Snyder
Keyword(s):  
T Cells ◽  
Salivary Gland ◽  
Nk Cells ◽  
Immune Evasion ◽  
Nk Cell ◽  
Hematopoietic Cells ◽  
Murine Cytomegalovirus ◽  
Viral Gene ◽  
Mhc I ◽  
Intranasal Infection

AbstractCytomegalovirus (CMV) infects most people in the world and causes clinically important disease in immune compromised and immune immature individuals. How the virus disseminates from the initial site of infection is poorly understood. We used an innovative approach, involving insertion of target sites for the haematopoietic specific miRNA miR-142-3p into an essential viral gene in murine cytomegalovirus. This virus was unable to disseminate to the salivary gland following intranasal infection, demonstrating a strict need for hematopoietic cells for dissemination from the natural site of infection. Viral immune evasion genes that modulate MHC-I expression and NKG2D activation were also required in this setting, as MCMV lacking these genes exhibited impaired dissemination of the viral genome to the salivary gland, and there was no detectable viral replication in the salivary gland. Depletion of T cells rescued the replication of this evasion-deficient virus in the salivary gland. Surprisingly however, the early dissemination to the salivary gland of this evasion-deficient virus, could be rescued by depletion of NK cells, but not T cells. These data are the first to show a profound loss of MCMV fitness in the absence of its MHC-I evasion genes and suggest that they protect the virus from NK cells during hematopoietic dissemination to the salivary gland, where they continued to need the three evasion genes to avoid T cell responses. Remarkably, we found that depletion of NK cells also freed the virus from the need to infect hematopoietic cells in order to reach the salivary gland. Thus, our data show that MCMV adapts to NK cell pressure after intranasal infection by using hematopoietic cells for dissemination while immune evasion genes protect the virus from NK cells during dissemination and from T cells within mucosal tissues.

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