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NK Cells and ⁺ T Cells Are Phenotypically and Functionally Defective due to Preferential Apoptosis in Patients with Atopic Dermatitis¹

Michie Katsuta^2,*, Yukio Takigawa^*, Momoko Kimishima^*, Miyuki Inaoka^*, Ryo Takahashi and Tetsuo Shiohara^*,

^* Department of Dermatology and Division of Flow Cytometry, Kyorin University School of Medicine, Tokyo, Japan

Innate immune cells mediate a first line of defense against pathogens and determine the nature of subsequent acquired immune responses, mainly by producing profound amounts of cytokines. Given these diverse tasks, it is predictable that defective NK and ⁺ T cell responses could be the underlying mechanism for the immunological alterations observed in atopic dermatitis (AD). Indeed, the frequencies of circulating NK cells and ⁺ T cells were profoundly reduced in AD patients. They also displayed a defective ability to sustain TNF- and IFN-, but not IL-4, production after in vitro stimulation, and the defect was restricted to innate immune cells. Surprisingly, on the depletion of CD14⁺ monocytes, this selective impairment of TNF- and IFN- production was restored to levels comparable to that observed in controls. Release of IL-10 from monocytes was not a major mechanism of the NK and ⁺ T cell dysfunction. Apoptosis as revealed by annexin V binding, was preferentially observed in NK and ⁺ T cells from AD patients when stimulated in the presence of monocytes, and depletion of monocytes significantly protected these cells from apoptotic cell death. Preferential apoptosis of NK cells by activated monocytes in AD patients was cell-contact-dependent. These results indicate that, once NK and ⁺ T cells in AD patients are in immediate contact with activated monocytes, these cells are specifically targeted for apoptosis, leading to the reduced type 1 cytokine production, thereby directing subsequent acquired immune responses toward a type-2 pattern and increasing susceptibility to infection.

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