Abstract
T‐cell receptors possess the unique ability to survey and respond to their permanently modified ligands, self HLA‐I molecules bound to non‐self peptides of various origin. This highly specific immune function is impaired following hematopoietic stem cell transplantation (HSCT) for a timespan of several months needed for the maturation of T‐cells. Especially, the progression of HCMV disease in immunocompromised patients induces life‐threatening situations. Therefore, the need for a new immune system that delivers vital and potent CD8+ T‐cells carrying TCRs that recognize even one human cytomegalovirus (HCMV) peptide/HLA molecule and clear the viral infection long term becomes obvious. The transcription and translation of HCMV proteins in the lytic cycle is a precisely regulated cascade of processes, therefore, it is a highly sensitive challenge to adjust the exact time point of HCMV‐peptide recruitment over self‐peptides. We utilized soluble HLA technology in HCMV‐infected fibroblasts and sequenced naturally sHLA‐A*24:02 presented HCMV‐derived peptides. One peptide of 14 AAs length derived from the IE2 antigen induced the strongest T‐cell responses; this peptide can be detected with a low ranking score in general peptide prediction databanks. These results highlight the need for elaborate and HLA‐allele specific peptide selection.
Highlights
The formation of the immunological synapse, composed of the HLA molecule, a peptide of pathogenic origin, the T-cell receptor, the CD8 co-receptor and among others, CD3 components, is very complex
The activation of a specific cytotoxic T-cell (CTL) is critically dependent from the recruitment and presentation of a pathogenic peptide, because every single peptide alters the structure of the presented peptide-HLA complex
Our study provides new insights into the origin and biochemical nature of viral peptides that are naturally recruited in human cytomegalovirus (HCMV) infected cells
Summary
The formation of the immunological synapse, composed of the HLA molecule, a peptide of pathogenic origin, the T-cell receptor, the CD8 co-receptor and among others, CD3 components, is very complex. Most peptides that have been studied are derived from the wellcharacterized phosphoprotein (pp)[65] or the immediatelyearly (IE)[1] protein, but not in all individuals responses against these two proteins are immunodominant.[36,37] Best studied are the pp[65] peptides NLVPMVATV and TPRVTGGGAM restricted to HLA-A*02:01 and HLAB*07:02, respectively, that usually induce strong T-cell responses.[38,39,40,41,42,43] the majority of these and other applied peptides are predicted by computational analysis.[36,44,45] It remains questionable if these peptides would ever be recruited through the patients peptide loading complex, selected by one HLA subtype and naturally presented by HCMV infected cells This might be an explanation for some unsuccessful T-cell transfers.[34,46,47]. The comprehensive analysis of a common HLA allele that constitutively present viral peptides during all stages of infection will help to improve T-cell therapies long term even for patients with virus susceptible HLA haplotypes
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