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

Abstract

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 γδ+ 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 γδ+ T cells were profoundly reduced in AD patients. They also displayed a defective ability to sustain TNF-α and IFN-γ, 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-α and IFN-γ 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 γδ+ T cell dysfunction. Apoptosis as revealed by annexin V binding, was preferentially observed in NK and γδ+ 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 γδ+ 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.

Changes in leukocyte counts, lymphocyte subpopulations and the mRNA expression of selected cytokines in the peripheral blood of dogs with atopic dermatitis

“…The percentage of NK cells did not significantly change in AD patients compared to healthy controls in the study of Bouloc et al (2000). However, another two papers reported a significant decline in patients with AD (Wehrmann et al 1990;Katsuta et al 2006) which is in accordance with our study.…”

“…Katsuta et al (2006) described the decline of this subpopulation in parallel with a significant decrease in the expression levels of IFN-γ and TNF-α mRNA, which however, was not confirmed in our study. In human medicine, NKcells in association with AD have been mentioned in several studies (Wehrmann et al 1990;Bouloc et al 2000;Katsuta et al 2006). The percentage of NK cells did not significantly change in AD patients compared to healthy controls in the study of Bouloc et al (2000).…”

“…The relative increase in the number of γδT-lymphocytes observed in our study was in contradiction to the only study describing the occurrence of this subpopulation in peripheral blood in association with AD. In this study, conducted in human patients, this decrease occurred together with a decrease in NK-cells due to elevated apoptosis induced by monocytes (Katsuta et al 2006). This difference could be explained by a different function of this subpopulation in dogs which could be controlled by other mechanisms.…”

“…These cells may not only be part of the natural defence of the body, but can also affect immune response polarisation via their cytokines (TNF-α and IFN-γ). Vice versa, their function can also be influenced by Th2 cytokine responses (Kos 1998;Lahn et al 1998;Katsuta et al 2006).…”

Pathological Role of Regulatory T Cells in the Initiation and Maintenance of Eczema Herpeticum Lesions

“…As shown in Fig. 1, a significant decrease in the frequencies of gd + T cells and CD56 + NK cells was found in AD patients, irrespective of EH, compared with healthy controls, a finding consistent with our previous report (15). In contrast, there were no significant differences in the frequencies of CD8 + T cells.…”