CD4 and neoplasm: Collectively, we demonstrate for the first time that by strategic combination of HLA class II-transgenic mice, immunization with recombinant Ad5 and combinatorial antigen-specific peptide library screening, CD4+ T cell epitopes from melanoma differentiation antigens can readily be defined, pointing to a broad applicability of this approach to target antigens of other tumor entities and to different HLA class II molecules even without prior characterization of their peptide binding motives.