Chemokine receptor requirements for epidermal T-cell trafficking

Inflamed skin contains CD4 T-cell subsets that express chemokine receptors CCR4, CCR6, and/or CCR10. Prior attempts to reveal the distinct role(s) of each receptor in T-cell trafficking to skin have not produced a coherent story. Different conclusions drawn by separate research groups are difficult to reconcile because of the disparate inflammation models used. Here we directly compare CD4 T cells from wild-type, CCR4(-/-), CCR6(-/-), and CCR10(-/-) mice in parallel assays of trafficking to skin. Our models require direct competition between wild-type and receptor-deficient populations for access to inflamed cutaneous sites. Major histocompatibility complex-peptide tetramers allowed us to identify antigen-specific endogenous long-term memory CD4 T cells within skin after multiple topical immunizations. We separately analyzed cells from the dermal and epidermal layers, allowing us to assess the involvement of each receptor in trafficking between dermis and epidermis. We found that CCR4 deficiency reduces accumulation of memory CD4 T cells in skin by approximately 20-fold, but neither CCR6 nor CCR10 deficiency yielded any detectable effects. Strikingly, no differences in dermal versus epidermal localization were observed for cells lacking any of these three receptors. Our findings raise the possibility that CCR6 and CCR10 play (as yet) unknown roles in cutaneous T-cell immunology, unrelated to skin-specific trafficking.