Limits...
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.

Show MeSH

Related in: MedlinePlus

M45-CTLs fail to control in vivo infection with mCMV-WT but resolve infection with mutant mCMV-Δm152. Immunocompromised C57BL/6 mice were infected (A) with mCMV-WT or (B) mCMV-Δm152. The in vivo antiviral function of M45-CTLs was tested by adoptive transfer. ∅, no cell transfer. Virus replication in organs was measured on day 12. For spleen and lung (left), virus titers were determined in organ homogenates by a virus plaque assay. The dotted line indicates the detection level. For the liver, the number of infected hepatocytes was determined by immunohistology specific for the intranuclear IE1 protein. Dot symbols represent data for individually numbered transfer recipients. Median values are marked.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC1887719&req=5

fig3: M45-CTLs fail to control in vivo infection with mCMV-WT but resolve infection with mutant mCMV-Δm152. Immunocompromised C57BL/6 mice were infected (A) with mCMV-WT or (B) mCMV-Δm152. The in vivo antiviral function of M45-CTLs was tested by adoptive transfer. ∅, no cell transfer. Virus replication in organs was measured on day 12. For spleen and lung (left), virus titers were determined in organ homogenates by a virus plaque assay. The dotted line indicates the detection level. For the liver, the number of infected hepatocytes was determined by immunohistology specific for the intranuclear IE1 protein. Dot symbols represent data for individually numbered transfer recipients. Median values are marked.

Mentions: These in vitro highly functional M45-CTLs were then tested for their antiviral in vivo efficacy by adoptive transfer into immunocompromised C57BL/6 mice infected with mCMV-WT (Fig. 3 A). Notably, the transferred cells were completely ineffectual in controlling virus replication in spleen, lung, and liver.


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-CTLs fail to control in vivo infection with mCMV-WT but resolve infection with mutant mCMV-Δm152. Immunocompromised C57BL/6 mice were infected (A) with mCMV-WT or (B) mCMV-Δm152. The in vivo antiviral function of M45-CTLs was tested by adoptive transfer. ∅, no cell transfer. Virus replication in organs was measured on day 12. For spleen and lung (left), virus titers were determined in organ homogenates by a virus plaque assay. The dotted line indicates the detection level. For the liver, the number of infected hepatocytes was determined by immunohistology specific for the intranuclear IE1 protein. Dot symbols represent data for individually numbered transfer recipients. Median values are marked.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: M45-CTLs fail to control in vivo infection with mCMV-WT but resolve infection with mutant mCMV-Δm152. Immunocompromised C57BL/6 mice were infected (A) with mCMV-WT or (B) mCMV-Δm152. The in vivo antiviral function of M45-CTLs was tested by adoptive transfer. ∅, no cell transfer. Virus replication in organs was measured on day 12. For spleen and lung (left), virus titers were determined in organ homogenates by a virus plaque assay. The dotted line indicates the detection level. For the liver, the number of infected hepatocytes was determined by immunohistology specific for the intranuclear IE1 protein. Dot symbols represent data for individually numbered transfer recipients. Median values are marked.
Mentions: These in vitro highly functional M45-CTLs were then tested for their antiviral in vivo efficacy by adoptive transfer into immunocompromised C57BL/6 mice infected with mCMV-WT (Fig. 3 A). Notably, the transferred cells were completely ineffectual in controlling virus replication in spleen, lung, and liver.

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