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Cytomegalovirus misleads its host by priming of CD8 T cells specific for an epitope not presented in infected tissues.

Holtappels R, Podlech J, Pahl-Seibert MF, Jülch M, Thomas D, Simon CO, Wagner M, Reddehase MJ - J. Exp. Med. (2003)

Bottom Line: Although the molecular mechanisms of CMV interference with the major histocompatibility complex class I pathway are long understood, surprisingly little evidence exists to support a role in vivo.Notably, the same cells protected C57BL/6 mice infected with an mCMV mutant in which immune evasion protein m152/gp40 is deleted.These data indicate that direct presentation or cross-presentation of an antigenic peptide by professional antigen-presenting cells can efficiently prime CD8 T cells that fail in protection against CMV organ disease because m152/gp40 prevents presentation of this peptide in pathogenetically relevant tissue cells.

View Article: PubMed Central - PubMed

Affiliation: Institute for Virology, Johannes Gutenberg-University, Hochhaus am Augustusplatz, 55101 Mainz, Germany.

ABSTRACT
Cytomegaloviruses (CMVs) code for several proteins that inhibit the presentation of antigenic peptides to CD8 T cells. Although the molecular mechanisms of CMV interference with the major histocompatibility complex class I pathway are long understood, surprisingly little evidence exists to support a role in vivo. Here we document the first example of the presentation of an antigenic peptide being blocked by a CMV immune evasion protein in organs relevant to CMV disease. Although this Db-restricted peptide, which is derived from the antiapoptotic protein M45 of murine CMV (mCMV), is classified as an immunodominant peptide based on response magnitude and long-term memory, adoptive transfer of M45 epitope-specific CD8 T cells did not protect against infection with wild-type mCMV. Notably, the same cells protected C57BL/6 mice infected with an mCMV mutant in which immune evasion protein m152/gp40 is deleted. These data indicate that direct presentation or cross-presentation of an antigenic peptide by professional antigen-presenting cells can efficiently prime CD8 T cells that fail in protection against CMV organ disease because m152/gp40 prevents presentation of this peptide in pathogenetically relevant tissue cells.

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Related in: MedlinePlus

M45-specific memory cells maintain antiviral function but are unable to prevent productive infection by the priming virus genotype. M45-TCR+ CD8+ memory cells were purified by cell sorting from a pool of spleen cells derived from 15 C57BL/6 mice at 4 mo after infection with mCMV-WT. The antiviral function was tested by adoptive transfer into immunocompromised C57BL/6 recipients infected with mutant virus mCMV-Δm152 or revertant virus mCMV-Δm152-rev. ∅, no cell transfer. On day 11, virus replication in the liver was quantitated by immunohistological detection of IE1 protein in the nuclei of infected hepatocytes. Dot symbols represent data for individual recipients. Median values are marked.
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fig5: M45-specific memory cells maintain antiviral function but are unable to prevent productive infection by the priming virus genotype. M45-TCR+ CD8+ memory cells were purified by cell sorting from a pool of spleen cells derived from 15 C57BL/6 mice at 4 mo after infection with mCMV-WT. The antiviral function was tested by adoptive transfer into immunocompromised C57BL/6 recipients infected with mutant virus mCMV-Δm152 or revertant virus mCMV-Δm152-rev. ∅, no cell transfer. On day 11, virus replication in the liver was quantitated by immunohistological detection of IE1 protein in the nuclei of infected hepatocytes. Dot symbols represent data for individual recipients. Median values are marked.

Mentions: Although the data have shown so far that M45-CTLs fail to control productive infection with mCMV-WT, M45-specific memory cells are maintained long-term in the host (Fig. 1). A critical question is whether the findings obtained with an in vitro–selected CTLL also apply to the memory CD8 T cell population present in the host. To answer this question, an adoptive transfer experiment was performed with M45-TCR+ CD8+ ex vivo memory cells sorted by using MHC-Ig hybrid molecules loaded with M45 peptide (Fig. 5) .


Cytomegalovirus misleads its host by priming of CD8 T cells specific for an epitope not presented in infected tissues.

Holtappels R, Podlech J, Pahl-Seibert MF, Jülch M, Thomas D, Simon CO, Wagner M, Reddehase MJ - J. Exp. Med. (2003)

M45-specific memory cells maintain antiviral function but are unable to prevent productive infection by the priming virus genotype. M45-TCR+ CD8+ memory cells were purified by cell sorting from a pool of spleen cells derived from 15 C57BL/6 mice at 4 mo after infection with mCMV-WT. The antiviral function was tested by adoptive transfer into immunocompromised C57BL/6 recipients infected with mutant virus mCMV-Δm152 or revertant virus mCMV-Δm152-rev. ∅, no cell transfer. On day 11, virus replication in the liver was quantitated by immunohistological detection of IE1 protein in the nuclei of infected hepatocytes. Dot symbols represent data for individual recipients. Median values are marked.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1887719&req=5

fig5: M45-specific memory cells maintain antiviral function but are unable to prevent productive infection by the priming virus genotype. M45-TCR+ CD8+ memory cells were purified by cell sorting from a pool of spleen cells derived from 15 C57BL/6 mice at 4 mo after infection with mCMV-WT. The antiviral function was tested by adoptive transfer into immunocompromised C57BL/6 recipients infected with mutant virus mCMV-Δm152 or revertant virus mCMV-Δm152-rev. ∅, no cell transfer. On day 11, virus replication in the liver was quantitated by immunohistological detection of IE1 protein in the nuclei of infected hepatocytes. Dot symbols represent data for individual recipients. Median values are marked.
Mentions: Although the data have shown so far that M45-CTLs fail to control productive infection with mCMV-WT, M45-specific memory cells are maintained long-term in the host (Fig. 1). A critical question is whether the findings obtained with an in vitro–selected CTLL also apply to the memory CD8 T cell population present in the host. To answer this question, an adoptive transfer experiment was performed with M45-TCR+ CD8+ ex vivo memory cells sorted by using MHC-Ig hybrid molecules loaded with M45 peptide (Fig. 5) .

Bottom Line: Although the molecular mechanisms of CMV interference with the major histocompatibility complex class I pathway are long understood, surprisingly little evidence exists to support a role in vivo.Notably, the same cells protected C57BL/6 mice infected with an mCMV mutant in which immune evasion protein m152/gp40 is deleted.These data indicate that direct presentation or cross-presentation of an antigenic peptide by professional antigen-presenting cells can efficiently prime CD8 T cells that fail in protection against CMV organ disease because m152/gp40 prevents presentation of this peptide in pathogenetically relevant tissue cells.

View Article: PubMed Central - PubMed

Affiliation: Institute for Virology, Johannes Gutenberg-University, Hochhaus am Augustusplatz, 55101 Mainz, Germany.

ABSTRACT
Cytomegaloviruses (CMVs) code for several proteins that inhibit the presentation of antigenic peptides to CD8 T cells. Although the molecular mechanisms of CMV interference with the major histocompatibility complex class I pathway are long understood, surprisingly little evidence exists to support a role in vivo. Here we document the first example of the presentation of an antigenic peptide being blocked by a CMV immune evasion protein in organs relevant to CMV disease. Although this Db-restricted peptide, which is derived from the antiapoptotic protein M45 of murine CMV (mCMV), is classified as an immunodominant peptide based on response magnitude and long-term memory, adoptive transfer of M45 epitope-specific CD8 T cells did not protect against infection with wild-type mCMV. Notably, the same cells protected C57BL/6 mice infected with an mCMV mutant in which immune evasion protein m152/gp40 is deleted. These data indicate that direct presentation or cross-presentation of an antigenic peptide by professional antigen-presenting cells can efficiently prime CD8 T cells that fail in protection against CMV organ disease because m152/gp40 prevents presentation of this peptide in pathogenetically relevant tissue cells.

Show MeSH
Related in: MedlinePlus