Skin resident T cells producing TNFalfa but not TH1, TH2, or Th17 cytokines: their posible role as immune sentinels in skin.

ABSTRACT BODY: The skin of a normal individual contains nearly 20 billion memory T cells, nearly twice as many as are present in the circulation. These T cells are polarized effector memory T cells that, from our current understanding, have arisen from recognition of their antigens within the skin. We previously reported that human skin contains significant numbers Th1, Th17 and Th2 cells. We report now that these T cell subsets are quiescent with respect to cytokine production when isolated from unstimulated skin and that additional signals (e.g., cellular proliferation) are required to unlock cytokine production. TNFα is a cytokine produced by both APC and subsets of effector T cells. We describe here a novel and previously undescribed population of skin resident T cells that produces TNFα alone, without concurrent production of IFNγ, IL-4 or IL-17. These cells comprise a mean 48% of the skin T cells resident in normal human skin. These T cells are CD45RO+ memory T cells, express CLA, CCR4 and CCR6 and have a diverse TCR repertoire. This T cell subset differs from the other cutaneous effector T cells in that half of these cells produce TNFα upon TCR triggering without a requirement for additional activating signals. TNFα T cells are the most numerous subset in normal human skin, outnumbering Th1, Th2 and Th17 T cells. TNFα has pleiotropic effects in the skin. TNFα induces maturation of dendritic cells, enhancing antigen presentation, and induces endothelial activation and chemokine production, leading to enhanced leukocyte recruitment. Skin TNFα T cells, specific for pathogens previously encountered in skin, may serve as antigen-specific immune sentinels. These T cells have the ability to rapidly produce TNFα upon re-exposure to cognate antigen, leading to activation and recruitment of both innate immune cells and other T cell subsets. Thus, they may serve to both initiate and amplify immune responses in skin