AbstractWe have previously demonstrated, in psoriatic skin lesions, the presence of a subset of dermal CD4+ T cells that produce interferon‐γ (IFN‐γ) in response to a mixture of cell wall proteins extracted from group A streptococci. However, the identity of the antigen(s) involved is unknown. To investigate the hypothesis that peptidoglycan (PG), the major constituent of the streptococcal cell wall, acts as a T cell activator in psoriasis, we performed in situ analysis to detect antigen‐presenting cells containing PG in lesional versus non‐lesional skin, and determined proliferation and IFN‐γ responses of lesional skin T cells. Increased numbers of PG‐containing cells were detected in the dermal papillae and cellular infiltrates of guttate and chronic plaque skin lesions compared with normal and non‐lesional psoriatic skin. A varying proportion of these were CD68+ macrophages, but the remaining cells did not double stain for either Langerhans' or dendritic cell markers. Psoriatic dermal streptococcal‐specific CD4+ T cell lines proliferated and produced IFN‐γ in a self HLA‐DR allele‐restricted manner in response to streptococcal PG, excluding mitogenic or superantigenic stimulation, but were unresponsive to staphylococcal PG. Similarly, psoriatic staphylococcus‐specific T cell lines recognized staphylococcal, but not streptococcal, PG by IFN‐γ production. The presence of PG‐containing macrophages in close association with PG‐specific CD4+ T cells in lesional skin suggests that PG may be responsible, at least in part, for T cell activation in psoriasis. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.