Peptides bound to HLA class II molecules are involved in epidermal T-cell activation, an integral part in the pathogenesis of psoriasis. To characterize the peptide repertoire displayed, HLA class II molecules were isolated from human HaCaT keratinocytes and from a split skin specimen of a patient with plaque-type psoriasis. Human neutrophil peptides (HNP) 1 and 2, belonging to the alpha-subfamily of defensins, were identified as dominant HLA class II bound self-peptides by means of HPLC and subsequent electrospray ionization mass spectrometry in both cases. Assuming the characteristic intramolecular disulfide bonds remain intact, an HLA class II binding motif can be modelled for HNP-1 and -2. Both peptides inhibited superantigen-mediated T-cell activation in vitro. In conclusion, HNP-1 and -2 are dominant HLA class II bound self-peptides displayed by keratinocytes in psoriasis. They are capable of interfering with superantigen-mediated T-cell activation. This might be a hint towards a possible role of alpha-defensins in the down-regulation of inflammation.