Human Endothelial Cell Presentation of Antigen and the Homing of Memory/Effector T Cells to Skin

A bstract : Dermal microvascular endothelial cells (ECs) form a continuous lining that normally bars blood‐borne T lymphocytes from entering the skin, but as part of the response to foreign antigen, dermal ECs undergo alterations in their surface proteins so as to provide signals to circulating T cells that lead to their activation and recruitment. Several observations suggest that human dermal microvascular ECs may help initiate cutaneous immune reactions by presentation of cognate antigens to circulating T memory cells: (1) antigen‐specific inflammatory responses in the skin, as in other organs, involve accumulation of memory and effector T cell populations that are enriched in cells specific for the eliciting antigen; (2) recall responses to intradermal protein antigens in the skin start very rapidly within two hours of challenge; (3) dermal microvascular ECs in humans and other large mammals basally display high levels of class I and class II MHC molecules, the only known purpose of which is to present antigenic peptides to lymphocytes; (4) the lumen of dermal capillaries are narrower than the diameter of circulating T cells, ensuring surface contact; and (5) cultured human ECs effectively present antigens to resting memory T cells isolated from the circulation. Upon contact with activated T cells or their secreted products (cytokines), dermal ECs themselves become activated, increasing their capacity to recruit memory and effector T cell populations in an antigen‐independent manner. Specifically, activated ECs express inducible leukocyte adhesion molecules such as E‐selectin, ICAM‐1, and VCAM‐1; and several lines of evidence, including neutralizing antibody experiments and gene knockouts, have supported a role of these molecules in T cell recruitment. Dermal ECs have unique expression patterns of adhesion molecules that can determine the subsets of memory T cells that are recruited into the skin. For example, slow internalization of E‐selectin allows more persistent expression of this protein on the surface of dermal ECs, favoring interactions with CLA‐1 + T cells. VCAM‐1 expression, normally confined to venular EC may extend to capillaries within the dermal papillae and contribute to epidermal inflammation, recruiting α 4 β 7 integrin‐expressing T cells that also express the cadherin‐binding integrin α E β 7 . New models involving transplantation of normal and genetically modified human dermal ECs into immunodeficient mice may be used to further explore these properties.