The role of Porphyromonas gingivalis cysteine proteinases (gingipains) in the evasion of host cell-mediated immunity has not been fully determined. In this study, modulation by gingipains of accessory and co-stimulatory molecule expression on human CD4(+) T cells was evaluated. Arg-gingipain rather than Lys-gingipain binds to resting CD4(+) T cells in the presence of serum. The constitutive expression of CD28 on T cells was slightly up-regulated following challenge with gingipains, whereas CD45 and CD3 were not affected. Binding of anti-CD2 and anti-CD4 monoclonal antibodies (mAbs) was reduced after challenge of T cells with gingipains, but restored to 50 and 100%, respectively, of control levels, after 48h of incubation in medium depleted of gingipains. The induced expression, by anti-CD3 mAb, of CTLA-4, CD25, and CD40 ligand (CD40L) was decreased following incubation of T cells with gingipains which also led to decreased response to anti-CD3 and anti-CD28 mAbs as shown by reduction of interleukin-2 (IL-2) production. Cumulatively, these results indicate that activated gingipains attach to T cells and preferentially cleave CD2 and CD4 molecules, with potential to impair T cell responses at periodontal sites.