The association of psoriasis with Streptococcus pyogenes throat infections suggests a potential antigenic target for the T cells that are known to infiltrate psoriatic skin. Streptococcal M protein share an extensive sequence homology with the human epidermal keratins. Keratin 17 (K17), while being mostly absent from uninvolved skin, is up-regulated in psoriatic lesions. Consequentially, M-protein-primed T cells may recognize up-regulated keratin epitopes via molecular mimicry. Using in vitro lymphocyte culture and cytokine flow cytometry we demonstrate that HLA-Cw*0602(+) psoriasis patients had significant CD8(+) T cell interferon (IFN)-gamma responses to peptides from the K17 and M6 protein selected on the basis of sequence homology and predicted HLA-Cw*0602 binding. These responses were about 10 times more frequent in the skin-homing cutaneous lymphocyte-associated antigen-expressing (CLA(+)) subset of CD8(+) T cells. CD4(+) T cells showed only borderline responses. CLA(+) CD8(+) T cells from Cw6(+) non-psoriatic individuals responded to some M6 peptides but rarely to K17 peptides. Cw6(-) psoriasis patients showed a response that was intermediate between Cw6(+) patients and controls. These findings indicate that psoriatic individuals have CD8(+) T cells that recognize keratin self-antigens and that epitopes shared by streptococcal M proteins and human keratins may be targets for the CD8(+) T cells that infiltrate psoriatic skin lesions.