Characterization of Melan-A reactive memory CD8+ T cells in a healthy donor

Abstract

Melan-A specific CD8+ T cells are thought to play an important role against the development of melanoma. Their in vivo expansion is often observed with advanced disease. In recent years, low levels of Melan-A reactive CD8+ T cells have also been found in HLA-A2 healthy donors, but these cells harbor naive characteristics and are thought to be mostly cross-reactive for the Melan-A antigen. Here, we report on a large population of CD8+ T cells reactive for the Melan-A antigen, identified in one donor with no evidence of melanoma. Interestingly, this population is oligoclonal and displays a clear memory phenotype. However, a detailed study of these cells indicated that they are unlikely to be directly specific for melanoma, so that their in vivo expansion may have been driven by an exogenous antigen. Screening of a Melan-A cross-reactive peptide library suggested that these cells may be specific for an epitope derived from a Mycobacterium protein, which would provide a further example of CD8+ T cell cross-reactivity between a pathogen antigen and a tumor antigen. Finally, we discuss potential perspectives regarding the role of such cells in heterologous immunity, by influencing the balance between protective immunity and pathology, e.g. in the case of melanoma development.

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

“…We observed both naïve and central memory MELOE-1-specific T cells in healthy donors and melanoma patients. The presence of MELOE-1 memory-specific T cells in healthy donors could result from a stimulation through cross-reactive peptides as previously described for the Melan-A antigen in one HLA-A2 1 healthy donor [29]. These Melan-Aspecific cells, likely generated through a stimulation with crossreactive peptides, turned out to be reactive against melanoma cells.…”

Germ Line-governed Recognition of a Cancer Epitope by an Immunodominant Human T-cell Receptor

“…1A). Molecular replacement was successful only in space group P4 3 , consistent with the presence of one molecule of the complex per asymmetric unit, and the resolution was sufficiently high to show that the interface between the two molecules was well ordered and contained well defined electron density. The final model showed ϳ96% of residues in the preferred and allowed regions of the Ramachandran plot and geometry consistent with the data resolution.…”

“…The MART-1 (1) protein, also known as Melan-A (2), is expressed by virtually all fresh melanoma tumor specimens and elicits natural CD8 ϩ T-cell responses (3,4) that can lead to spontaneous disease regression (reviewed in Ref. 5).…”

Tumor Antigen–Specific FOXP3+ CD4 T Cells Identified in Human Metastatic Melanoma: Peptide Vaccination Results in Selective Expansion of Th1-like Counterparts

“…We have shown that the natural Melan-A [26][27][28][29][30][31][32][33][34][35] decapeptide binds weakly to the HLA-A2 molecule because of the lack of a strong anchor residue at position P2. The replacement of Ala at position 27 for Leu results in enhanced binding to HLA-A2, in 2-to 3-log increase of its relative antigenicity and, more importantly, to an increased immunogenicity (17).…”

“…Moreover, HLA-DQ6/ Melan-A 25-36 multimers directly identified specific CD4 T cells by flow cytometry. Interestingly, this optimal CD4 T-cell epitope fully encompasses the HLA-A2-restricted decapeptide Melan-A [26][27][28][29][30][31][32][33][34][35] . In this report, we used HLA-DQ6/Melan-A peptide multimers to analyze in detail Melan-A-specific CD4 T-cell responses in healthy individuals (HD) and a cohort of HLA-A*0201 metastatic melanoma patients who shared expression of the HLA-DQB1*0602 allele.…”