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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