Melan-A/MART-151–73represents an immunogenic HLA-DR4-restricted epitope recognized by melanoma-reactive CD4+T cells

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Abstract
The human Melan-A/MART-1 gene encodes an HLA-A2-restricted peptide epitope recognized by melanoma-reactive CD8+ cytotoxic T lymphocytes. Here we report that this gene also encodes at least one HLA-DR4-presented peptide recognized by CD4+ T cells. The Melan-A/MART-151–73 peptide was able to induce the in vitro expansion of specific CD4+ T cells derived from normal DR4+ donors or from DR4+ patients with melanoma when pulsed onto autologous dendritic cells. CD4+ responder T cells specifically produced IFN-γ in response to, and also lysed, T2.DR4 cells pulsed with the Melan-A/MART-151–73 peptide and DR4+ melanoma target cells naturally expressing the Melan-A/MART-1 gene product. Interestingly, CD4+ T cell immunoreactivity against the Melan-A/MART-151–73 peptide typically coexisted with a high frequency of anti-Melan-A/MART-127–35 reactive CD8+ T cells in freshly isolated blood harvested from HLA-A2+/DR4+ patients with melanoma. Taken together, these data support the use of this Melan-A/MART-1 DR4-restricted melanoma epitope in future immunotherapeutic trials designed to generate, augment, and quantitate specific CD4+ T cell responses against melanoma in vivo.

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