scholarly journals Class I Major Histocompatibility Complex Presentation of Antigens That Escape from the Parasitophorous Vacuole of Toxoplasma gondii

2005 ◽  
Vol 73 (2) ◽  
pp. 703-711 ◽  
Author(s):  
Marc-Jan Gubbels ◽  
Boris Striepen ◽  
Nilabh Shastri ◽  
Mustafa Turkoz ◽  
Ellen A. Robey
Keyword(s):  
Major Histocompatibility Complex ◽  
Toxoplasma Gondii ◽  
Host Cell ◽  
Parasitophorous Vacuole ◽  
T Cell Response ◽  
Class I ◽  
Peptide Transporter ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Infected Cells

ABSTRACT The intracellular parasite Toxoplasma gondii, the causative agent of toxoplasmosis, induces a protective CD8 T-cell response in its host; however, the mechanisms by which T. gondii proteins are presented by the class I major histocompatibility complex remain largely unexplored. T. gondii resides within a specialized compartment, the parasitophorous vacuole, that sequesters the parasite and its secreted proteins from the host cell cytoplasm, suggesting that an alternative cross-priming pathway might be necessary for class I presentation of T. gondii antigens. Here we used a strain of T. gondii expressing yellow fluorescent protein and a secreted version of the model antigen ovalbumin to investigate this question. We found that presentation of ovalbumin secreted by the parasite requires the peptide transporter TAP (transporter associated with antigen processing) and occurs primarily in actively infected cells rather than bystander cells. We also found that dendritic cells are a major target of T. gondii infection in vivo and account for much of the antigen-presenting activity in the spleen. Finally, we obtained evidence that Cre protein secreted by T. gondii can mediate recombination in the nucleus of the host cell. Together, these results indicate that Toxoplasma proteins can escape from the parasitophorous vacuole into the host cytoplasm and be presented by the endogenous class I pathway, leading to direct recognition of infected cells by CD8 T cells.

scholarly journals A Human Herpesvirus 7 Glycoprotein, U21, Diverts Major Histocompatibility Complex Class I Molecules to Lysosomes

2001 ◽  
Vol 75 (24) ◽  
pp. 12347-12358 ◽  
Author(s):  
Amy W. Hudson ◽  
Peter M. Howley ◽  
Hidde L. Ploegh
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Cytotoxic T Lymphocytes ◽  
Human Herpesvirus ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Infected Cells ◽  
Immune Detection

ABSTRACT All members of the herpesvirus family persist in their host throughout life. In doing so, herpesviruses exploit a surprising number of different strategies to evade the immune system. Human herpesvirus 7 (HHV-7) is a relatively recently discovered member of the herpesvirus family, and little is known about how it escapes immune detection. Here we show that HHV-7 infection results in premature degradation of major histocompatibility complex class I molecules. We identify and characterize a protein from HHV-7, U21, that binds to and diverts properly folded class I molecules to a lysosomal compartment. Thus, U21 is likely to function in the normal course of HHV-7 infection to downregulate surface class I molecules and prevent recognition of infected cells by cytotoxic T lymphocytes.

scholarly journals Characterization of a Murine Cytomegalovirus Class I Major Histocompatibility Complex (MHC) Homolog: Comparison to MHC Molecules and to the Human Cytomegalovirus MHC Homolog

1998 ◽  
Vol 72 (1) ◽  
pp. 460-466 ◽  
Author(s):  
Tara L. Chapman ◽  
Pamela J. Bjorkman
Keyword(s):  
Major Histocompatibility Complex ◽  
Heavy Chain ◽  
Class I ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Endogenous Peptides ◽  
Β2 Microglobulin ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Infected Cells

ABSTRACT Both human and murine cytomegaloviruses (HCMV and MCMV) down-regulate expression of conventional class I major histocompatibility complex (MHC) molecules at the surfaces of infected cells. This allows the infected cells to evade recognition by cytotoxic T cells but leaves them susceptible to natural killer cells, which lyse cells that lack class I molecules. Both HCMV and MCMV encode class I MHC heavy-chain homologs that may function in immune response evasion. We previously showed that a soluble form of the HCMV class I homolog (UL18) expressed in Chinese hamster ovary cells binds the class I MHC light-chain β2-microglobulin and a mixture of endogenous peptides (M. L. Fahnestock, J. L. Johnson, R. M. R. Feldman, J. M. Neveu, W. S. Lane, and P. J. Bjorkman, Immunity 3:583–590, 1995). Consistent with this observation, sequence comparisons suggest that UL18 contains the well-characterized groove that serves as the binding site in MHC molecules for peptides derived from endogenous and foreign proteins. By contrast, the MCMV homolog (m144) contains a substantial deletion within the counterpart of its α2 domain and might not be expected to contain a groove capable of binding peptides. We have now expressed a soluble version of m144 and verified that it forms a heavy chain–β2-microglobulin complex. By contrast to UL18 and classical class I MHC molecules, m144 does not associate with endogenous peptides yet is thermally stable. These results suggest that UL18 and m144 differ structurally and might therefore serve different functions for their respective viruses.

scholarly journals High Viremia Is Associated with High Levels of In Vivo Major Histocompatibility Complex Class I Downregulation in Rhesus Macaques Infected with Simian Immunodeficiency Virus SIVmac239

2010 ◽  
Vol 84 (10) ◽  
pp. 5443-5447 ◽  
Author(s):  
Thomas C. Friedrich ◽  
Shari M. Piaskowski ◽  
Enrique J. León ◽  
Jessica R. Furlott ◽  
Nicholas J. Maness ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Ex Vivo ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Infected Cells

ABSTRACT Human and simian immunodeficiency viruses (HIV and SIV) downregulate major histocompatibility complex class I (MHC-I) molecules from the surface of infected cells. Although this activity is conserved across viral isolates, its importance in AIDS pathogenesis is not clear. We therefore developed an assay to detect the level of MHC-I expression of SIV-infected cells directly ex vivo. Here we show that the extent of MHC-I downregulation is greatest in SIVmac239-infected macaques that never effectively control virus replication. Our results suggest that a high level of MHC-I downregulation is a hallmark of fast disease progression in SIV infection.

scholarly journals The Selective Downregulation of Class I Major Histocompatibility Complex Proteins by HIV-1 Protects HIV-Infected Cells from NK Cells

Immunity ◽  
1999 ◽  
Vol 10 (6) ◽  
pp. 661-671 ◽  
Author(s):  
George B Cohen ◽  
Rajesh T Gandhi ◽  
Daniel M Davis ◽  
Ofer Mandelboim ◽  
Benjamin K Chen ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Class I ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Infected Cells ◽  
Hiv 1 ◽  
Major Histocompatibility Complex Proteins

scholarly journals Peptide size selection by the major histocompatibility complex-encoded peptide transporter.

1994 ◽  
Vol 179 (5) ◽  
pp. 1613-1623 ◽  
Author(s):  
F Momburg ◽  
J Roelse ◽  
G J Hämmerling ◽  
J J Neefjes
Keyword(s):  
Amino Acids ◽  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Class I ◽  
Peptide Transporter ◽  
Major Histocompatibility ◽  
Permeabilized Cells ◽  
Histocompatibility Complex ◽  
Tlc Analysis ◽  
Mhc Class I Molecules

The major histocompatibility complex (MHC)-encoded heterodimeric TAP1/TAP2 transporter (TAP) translocates cytosolic peptides into the lumen of the endoplasmic reticulum (ER), where peptides of 8 to 11 amino acids long associate with MHC class I molecules. We have studied the selectivity of peptide translocation by TAP in streptolysin O-permeabilized cells using glycosylatable, radioiodinated model peptides to detect import into the ER lumen. TAP-dependent translocation of a radiolabeled nonamer peptide was most efficiently inhibited by unlabeled 9- to 11-mer peptides. Peptides between 7 and 40 amino acids long all could inhibit transport, the longer peptides being least effective. Also, peptides shorter than eight amino acids were inefficiently translocated. The use of directly labeled length variants in translocation assays and TLC analysis of the transported material revealed two pathways for translocation: short peptides (7 to 13 amino acids long) were translocated without prior modification. In contrast, transport of longer peptides was not effective. Instead such peptides were clipped by cytosolic peptidases before efficient transport. Our data suggest that TAP preferentially translocates peptides of appropriate length for class I binding. Furthermore, TAP-translocated peptides were rapidly released from the ER unless they were trapped there by being glycosylated or by binding to MHC class I molecules.

scholarly journals Modulation of Natural Killer Cell Cytotoxicity in Human Cytomegalovirus Infection: The Role of Endogenous Class I Major Histocompatibility Complex and a Viral Class I Homolog

1998 ◽  
Vol 187 (10) ◽  
pp. 1681-1687 ◽  
Author(s):  
Clement C. Leong ◽  
Tara L. Chapman ◽  
Pamela J. Bjorkman ◽  
Danuska Formankova ◽  
Edward S. Mocarski ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Class I ◽  
Inhibitory Receptors ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Infected Cells

Natural killer (NK) cells have been implicated in early immune responses against certain viruses, including cytomegalovirus (CMV). CMV causes downregulation of class I major histocompatibility complex (MHC) expression in infected cells; however, it has been proposed that a class I MHC homolog encoded by CMV, UL18, may act as a surrogate ligand to prevent NK cell lysis of CMV-infected cells. In this study, we examined the role of UL18 in NK cell recognition and lysis using fibroblasts infected with either wild-type or UL18 knockout CMV virus, and by using cell lines transfected with the UL18 gene. In both systems, the expression of UL18 resulted in the enhanced killing of target cells. We also show that the enhanced killing is due to both UL18-dependent and -independent mechanisms, and that the killer cell inhibitory receptors (KIRs) and CD94/NKG2A inhibitory receptors for MHC class I do not play a role in affecting susceptibility of CMV-infected fibroblasts to NK cell–mediated cytotoxicity.

scholarly journals Coxsackievirus B3 Proteins Directionally Complement Each Other To Downregulate Surface Major Histocompatibility Complex Class I

2007 ◽  
Vol 81 (13) ◽  
pp. 6785-6797 ◽  
Author(s):  
Christopher T. Cornell ◽  
William B. Kiosses ◽  
Stephanie Harkins ◽  
J. Lindsay Whitton
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Golgi Complex ◽  
Coxsackievirus B3 ◽  
T Cell Response ◽  
Surface Proteins ◽  
Class I ◽  
Major Histocompatibility ◽  
Viral Protein Synthesis ◽  
Histocompatibility Complex

ABSTRACT Picornaviruses carry a small number of proteins with diverse functions that subvert and exploit the host cell. We have previously shown that three coxsackievirus B3 (CVB3) proteins (2B, 2BC, and 3A) target the Golgi complex and inhibit protein transit. Here we investigate these effects in more detail and evaluate the distribution of major histocompatibility complex (MHC) class I molecules, which are critical mediators of the CD8+ T-cell response. We report that concomitant with viral protein synthesis, MHC class I surface expression is rapidly downregulated during infection. However, this phenomenon may not result solely from inhibition of anterograde trafficking; we propose a new mechanism whereby the CVB3 2B and 2BC proteins upregulate the internalization of MHC class I (and possibly other surface proteins), perhaps by focusing of endocytic vesicles at the Golgi complex. Thus, our findings indicate that CVB3 carries at least three nonstructural proteins that directionally complement one another; 3A disrupts the Golgi complex to inhibit anterograde transport, while 2B and/or 2BC upregulates endocytosis, rapidly removing proteins from the cell surface. Taken together, these effects may render CVB3-infected cells invisible to CD8+ T cells and untouchable by many antiviral effector molecules. This has important implications for immune evasion by CVB3.

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