Qualitative difference between the cytotoxic T lymphocyte responses to melanocyte antigens in melanoma and vitiligo

Abstract

Vitiligo is a skin disorder characterized by depigmented macules secondary to melanocyte loss. An unusual facet is its relation to melanoma: Cytotoxic T lymphocytes directed to melanocyte antigens are found in both conditions and imply a breakdown of tolerance, yet the resulting immune reaction is the opposite. The mechanisms at the basis of these opposite effects are not known. Here, we performed a direct comparison of whole melanocyte-specific T cell populations in the two diseases. We demonstrate that neither precursor frequencies of Melan-A/MART-1-specific T lymphocytes nor their status of activation differ significantly. However, by using a tetramer-based T cell receptor down-regulation assay, we documented a higher affinity of vitiligo T cells. We calculated that the peptide concentration required for 50% of maximal receptor downregulation differed by 6.5-fold between the two diseases. Moreover, only vitiligo T cells were capable of efficient receptor down-regulation and IFN-c production in response to HLA-matched melanoma cells, suggesting that this difference in receptor affinity is physiologically relevant. The differences in receptor affinity and tumor reactivity were confirmed by analyzing Melan-A/MART-1-specific clones established from the two diseases. Our results suggest that the quality, and not the quantity, of the melanocytespecific cytotoxic responses differs between the two pathologies.

Vitiligo, reactive oxygen species and T-cells

“…However, only vitiligo cells showed T-cell-receptor down-regulation and IFN-γ production after exposure to HLA-matched melanoma cells, suggesting a qualitative difference in receptor affinity in the two groups. Vitiligo has been considered the effective variant of melanoma immunity [216,217]. Van den Boorn et al [218] expanded on all these findings in 2009: their study showed a prominent role for T-cells in vitiligo pathogenesis, being causative rather than just a consequence of other stimuli.…”

“…One patient showed Melan-A and tyrosinase specificity after in vitro re-stimulation [215]. Palermo et al [216] utilized the tetramer technique with peripheral blood of patients with vitiligo or melanoma and showed the presence of Melan-A-specific cytotoxic T-cells at similar levels in both HLA-A2-matched groups. However, only vitiligo cells showed T-cell-receptor down-regulation and IFN-γ production after exposure to HLA-matched melanoma cells, suggesting a qualitative difference in receptor affinity in the two groups.…”

Listeria monocytogenesas a vector for tumor-associated antigens for cancer immunotherapy

“…In most cases, central tolerance operates to limit the immune response by negatively selecting highly responsive T cells during development in the thymus. Responsive cells to selfantigens that do survive and leave the thymus to populate the periphery are generally cells that are of lower affinity for selfpeptides and as such are much more difficult to stimulate [57,58]. Furthermore, peripheral tolerance in the form of T regs (CD4 + CD25 + ) and/or T-cell anergy prevent selfresponsive T cells from targeting random cells and in essence triggering an auto-immune response [59].…”

T-Cell Avidity and Tuning: The Flexible Connection Between Tolerance and Autoimmunity

“…However, melanoma-infiltrating T cells display a profound reduction in the affinity for their antigens. Additionally, T cells from vitiligo patients were capable of efficient IFN-γ production and TCR downregulation in response to HLA-matched melanoma cells, whereas melanoma-derived T cells were not [86]. These findings suggest that in melanoma the slow rise in peripheral antigen presentation of melanocyte antigens, resulting from progressive tumor necrosis, most likely tunes responsive T cells.…”