Phosphorylated Peptides Are Naturally Processed and Presented by Major Histocompatibility Complex Class I Molecules in Vivo

Abstract

Posttranslational modification of peptide antigens has been shown to alter the ability of T cells to recognize major histocompatibility complex (MHC) class I–restricted peptides. However, the existence and origin of naturally processed phosphorylated peptides presented by MHC class I molecules have not been explored. By using mass spectrometry, significant numbers of naturally processed phosphorylated peptides were detected in association with several human MHC class I molecules. In addition, CD8+ T cells could be generated that specifically recognized a phosphorylated epitope. Thus, phosphorylated peptides are part of the repertoire of antigens available for recognition by T cells in vivo.

Identification of tumor-associated, MHC class II-restricted phosphopeptides as targets for immunotherapy

“…CD8 ϩ T cells immunized to specifically recognize these phosphopeptides are also capable of recognizing intact human tumor cells, suggesting that phosphopeptides may represent a new class of targets for cancer immunotherapy (5,6). In these studies and others, T cell discrimination of the phosphopeptide versus its nonphosphorylated counterpart was observed, indicating that phosphorylation can influence peptide immunogenicity (5)(6)(7)(8)(9)(10)(11)(12)(13). Recent crystal structural definition of phosphorylated peptide-HLA-A2 complexes demonstrated direct and indirect interactions of the phosphoresidue with the MHC molecule, often significantly increasing the affinity of the phosphopeptide for MHC I. Additionally, phosphoresidues were solvent-exposed, suggesting the potential for direct interactions with the T cell receptor (14,15).…”

“…Phosphorylation cascades are often dysregulated during malignant transformation, leading to uncontrolled proliferation, invasion of normal tissues, and distant metastasis (3,4). Limited but growing evidence has shown that tumor-associated phosphoproteins processed intracellularly through an endogenous pathway can give rise to phosphopeptides complexed to MHC I molecules, which are displayed on the cell surface (5,6). CD8 ϩ T cells immunized to specifically recognize these phosphopeptides are also capable of recognizing intact human tumor cells, suggesting that phosphopeptides may represent a new class of targets for cancer immunotherapy (5,6).…”

“…Limited but growing evidence has shown that tumor-associated phosphoproteins processed intracellularly through an endogenous pathway can give rise to phosphopeptides complexed to MHC I molecules, which are displayed on the cell surface (5,6). CD8 ϩ T cells immunized to specifically recognize these phosphopeptides are also capable of recognizing intact human tumor cells, suggesting that phosphopeptides may represent a new class of targets for cancer immunotherapy (5,6). In these studies and others, T cell discrimination of the phosphopeptide versus its nonphosphorylated counterpart was observed, indicating that phosphorylation can influence peptide immunogenicity (5)(6)(7)(8)(9)(10)(11)(12)(13).…”

Cutting Edge: MHC Class II-Restricted Peptides Containing the Inflammation-Associated Marker 3-Nitrotyrosine Evade Central Tolerance and Elicit a Robust Cell-Mediated Immune Response

“…If conversion of tyrosine to nitrotyrosine in autologous proteins can render these proteins recognizable as immunogenic autoantigens, this could have important implications for autoimmune diseases. Recent studies have indicated that a host of post-translational modifications, including glycosylation (19,20), phosphorylation (21,22), and cysteinylation (23,24), can all affect T cell immunoreactivity. Indeed, it has been proposed that these modifications may play a role in the initiation and/or maintenance of autoimmune disease by contributing to the breakdown of immunological tolerance (25,26).…”

MHC class I and class II presentation of tumor antigen in retrovirally and adenovirally transduced dendritic cells

“…These epitopes would also be subjected to normal posttranslational processing, which has been shown to be important for presentation of some cysteinylated peptides, phosphopeptides, and glycopeptides to T cells. 22,23 Finally, because the protein continues to be expressed over time, transduced DCs may sustain epitope presentation longer than their peptide-pulsed counterparts.…”