Editors' ChoiceIMMUNITY

Immunity Is But Skin Deep: Context Is Everything

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Science Translational Medicine  06 Jun 2012:
Vol. 4, Issue 137, pp. 137ec101
DOI: 10.1126/scitranslmed.3004399

Skin is the first line of defense against infection. When this protective barrier is breached, the immune system must jump into action to fight the prospective invader. However, the nature of a protective immune response depends on the type of stimulus: Pathogens elicit activation of host-defense mechanisms, whereas steady-state conditions may induce immune suppression and tolerance. How the skin initiates immunity to pathogens, but tolerance to benign antigens, is not well understood. Now, a study of human epidermal Langerhans cells (LCs) by Seneschal et al. reveals that these specialized dendritic cells control skin resident memory T lymphocyte responses, directing either immunity or tolerance.

Human skin contains billions of resident memory T lymphocytes capable of rapidly responding to antigens penetrating the skin surface. Seneschal et al. report that human LCs could induce either T cell tolerance or activation of T cell–mediated host defense in these skin resident cells. During steady state, LCs stimulated functionally competent immunosuppressive regulatory T cells, which are likely responsible for maintaining tolerance. However, in the presence of foreign antigen, isolated human LCs had a high capacity to specifically stimulate memory T cell proliferation. This differential induction may be dose dependent; low-dose antigen from Candida albicans, a common skin microbe, induced regulatory T cells, whereas high doses resulted in effector T cell proliferation. Thus, human skin LCs may function as immune commanders, deciding between either inducing tolerance to benign stimulants or activating the T cell immune response to potential infection.

Breaches in skin protection can lead to localized infections or a portal of entry for pathogen dissemination. Alternatively, a breakdown in immune tolerance may be critical to the development of autoimmune diseases. This study suggests that context is critical for determining which of these responses predominate.

J. Seneschal et al., Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 36, 873–884 (2012). [Abstract]

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