. 74:7496-7507, 2000). It was proposed that these cells represent antiviral "standby" memory cells whose functional role might be to help prevent reactivation of latent virus. The pool of pulmonary CD8 T cells was composed of two subsets defined by the T-cell activation marker L-selectin (CD62L): a CD62Lhi subset of quiescent memory cells, and a CD62L lo subset of recently resensitized memory-effector cells. In this study, we have continued this line of investigation by quantitating CD8 T cells specific for the three currently published antigenic peptides of mCMV: peptide YPHFMPTNL processed from the immediate-early protein IE1 (pp89), and peptides YGPSLYRRF and AYAGLFTPL, derived from the early proteins m04 (gp34) and M84 (p65), respectively. IE1-specific CD8 T cells dominated in acute-phase pulmonary infiltrates and were selectively enriched in latently infected lungs. Notably, most IE1-specific CD8 T cells were found to belong to the CD62L lo subset representing memory-effector cells. This finding is in accordance with the interpretation that IE1-specific CD8 T cells are frequently resensitized during latent infection of the lungs and may thus be involved in the maintenance of mCMV latency.In human cytomegalovirus (hCMV) infection after bone marrow transplantation (BMT), recovery from CMV disease correlates with efficient reconstitution of CD8 T cells (50). Preemptive cytoimmunotherapy by adoptive transfer of hCMVspecific CD8 T-cell clones was found to be beneficial in that it reduced the incidence of CMV disease in BMT recipients (51, 56). Proof of principle for the protective effect of antiviral CD8 T cells was provided by the model of murine CMV (mCMV) infection of BALB/c mice subjected to hematoablative treatment. Early experiments performed in the absence of BMT documented an antiviral and protective function of adoptively transferred mCMV-specific CD8 T cells in the lungs as well as in other target organs of the disease (44, 46, 48; for a review, see reference 23). More recently, the course of mCMV infection was analyzed in the specific context of hematolymphopoietic reconstitution after either syngeneic BMT (18,38,39) or BMT performed across a single major histocompatibility complex (MHC) class I antigen disparity (1). Prevention of a disseminated and fulminant interstitial CMV pneumonia by the antiviral function of endogenously reconstituted CD8 T cells was inferred from the following observations: (i) CD8 T cells rather than CD4 T cells were recruited to infected lungs much more efficiently than to uninfected lungs (18); (ii) lung-infiltrating, blastoid CD62L lo CD8 T cells were not randomly distributed in lung tissue but were found to colocalize with infected lung cells in inflammatory foci, thereby secluding the infected cells from health tissue (18, 38); (iii) when isolated from the infiltrates, these activated CD8 T cells exerted ex vivo cytolytic activity against infected target cells (18) and secreted gamma interferon (IFN-␥) upon polyclonal triggering via CD3ε (38); (iv) the kinetics of infilt...
The importance of CD8 T cells for the control of cytomegalovirus (CMV) infection has raised interest inNotably, CD8 T-cell lines of both specificities protected against acute infection upon adoptive transfer. In contrast, the natural immune response to acute infection in draining lymph nodes and in the lungs indicated a somewhat broader specificity repertoire. We conclude that the low number of antigenic peptides identified so far for CMVs reflects a focused memory repertoire, and we predict that more antigenic peptides will be disclosed by analysis of the acute immune response.
Murine cytomegalovirus encodes three regulators of antigen presentation to antiviral CD8 T cells. According to current paradigms, all three regulators are committed to the inhibition of the presentation of antigenic peptides. Whereas m152/gp40 catalyzes the retention of peptide-loaded major histocompatibility complex (MHC) class I molecules in a cis-Golgi compartment, m06/gp48 binds stably to class I molecules and directs them into the cellular cargo-sorting pathway of lysosomal degradation. Regulator m04/gp34 also binds stably to class I molecules, but unlike m152 and m06, it does not downmodulate MHC class I cell surface expression. It has entered the literature as a direct inhibitor of T-cell recognition of the MHC-peptide complex at the cell surface. In this work, we have studied the presentation of antigenic viral peptides in cells infected with a comprehensive set of mutant viruses expressing the three regulators separately as well as in all possible combinations. The results redefine m04 as a positive regulator dedicated to the facilitation of antigen presentation. When expressed alone, it did not inhibit T-cell recognition, and when expressed in the presence of m152, it restored antigen presentation by antagonizing the inhibitory function of m152. Its intrinsic positive function, however, was antagonized and even slightly overcompensated for by the negative regulator m06. In an adoptive cell transfer model, the opposing forces of the three regulators were found to govern immune surveillance in the infected host. While negative regulators, also known as immunoevasins, are common, the existence of a positive regulator is without precedent and indicates an intriguing genetic potential of this virus to influence antigen presentation.
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 D b -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.
Reconstitution of antiviral CD8 T cells is essential for controlling cytomegalovirus (CMV) infectionThe L d -restricted immediate-early 1 (IE1) peptide 168-YPHFMPTNL-176 of murine cytomegalovirus (mCMV) was the first antigenic peptide to be identified for a herpesvirus (50). The IE1 protein derived from open reading frame (ORF) m123, an intranuclear phosphoprotein which exists in molecular species of 89 and 76 kDa (32), is expressed in the IE phase of viral gene expression and performs regulatory and transactivating functions (12,31,39). It is encoded in transcription unit ie1/3 of which mRNAs specifying proteins IE1 (encoded by exons 2, 3, and 4) and IE3 (encoded by exons 2, 3, and 5) are generated by differential splicing (31, 39). The IE1 protein is processed to yield peptide 168-YPHFMPTNL-176 and an Nterminally elongated precursor 166-DMYPHFMPTNL-176 by the constitutive proteasome and, more efficiently, by the immunoproteasome, with only the precursor being translocated into the lumen of the endoplasmic reticulum for major histocompatibility complex class I (MHC-I) loading (36). N-terminal trimming finally leads to the IE1 peptide presented by the MHC-I molecule L d (reviewed in reference 45). Based on the frequency of IE1 epitope-specific CD8 T cells primed during acute infection and on the establishment of long-term IE1-specific memory, the IE1 peptide was classified as one of just two immunodominant MHC-I-restricted antigenic peptides in the H-2 d haplotype (25). Owing to MHC polymorphism, it is evident that immunodominance of peptides and the proteins from which they are derived cannot be extrapolated to other haplotypes in the same animal species. This is all the more true for extrapolation from mCMV to antigenic peptides of human cytomegalovirus (hCMV) presented by HLA molecules. Thus, although an early report by Borysiewicz et al. (4) had indicated the CD8 T-cell immunogenicity of the hCMV IE1 ortholog, the predictive value of the BALB/c mouse model in terms of the role of IE proteins in immunity to CMVs has been debated for a long time, until more recently the IE1 immunogenicity in humans was revisited with unbiased new methodology (10,14,33,34). Most intriguingly, in a comprehensive pangenomic search for antigenic ORFs of hCMV by using overlapping peptides and by covering all major HLA molecules present in the human population, Louis Picker and colleagues identified ORF UL123 encoding the IE1 protein as one of the top three antigen-encoding ORFs of hCMV that are most frequently detected by HLA class I-restricted human CD8 T cells (L. Picker, "T cell recognition of hCMV in natural human infection: pan-genome analysis of immunogenic open reading frames," Instituto Juan March de Estudios e Investigaciones workshop "Immunodominance: the key to understanding and manipulating CD8 ϩ T cell responses
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