CD1dhiPD-L1hiCD27+ Regulatory Natural Killer Subset Suppresses Atopic Dermatitis

Abstract

Effector and regulatory functions of various leukocytes in allergic diseases have been well reported. Although the role of conventional natural killer (NK) cells has been established, information on its regulatory phenotype and function are very limited. Therefore, the objective of this study was to investigate the phenotype and inhibitory functions of transforming growth factor (TGF)-β-producing regulatory NK (NKreg) subset in mice with MC903-induced atopic dermatitis (AD). Interestingly, the population of TGF-β-producing NK cells in peripheral blood monocytes (PBMCs) was decreased in AD patients than in healthy subjects. The number of TGF-β+ NK subsets was decreased in the spleen or cervical lymph node (cLN), but increased in ear tissues of mice with AD induced by MC903 than those of normal mice. We further observed that TGF-β+ NK subsets were largely included in CD1dhiPD-L1hiCD27+ NK cell subset. We also found that numbers of ILC2s and TH2 cells were significantly decreased by adoptive transfer of CD1dhiPD-L1hiCD27+ NK subsets. Notably, the ratio of splenic Treg per TH2 was increased by the adoptive transfer of CD1dhiPD-L1hiCD27+ NK cells in mice. Taken together, our findings demonstrate that the TGF-β-producing CD1dhiPD-L1hiCD27+ NK subset has a previously unrecognized role in suppressing TH2 immunity and ILC2 activation in AD mice, suggesting that the function of TGF-β-producing NK subset is closely associated with the severity of AD in humans.

KIR Allelic Variation and the Remission of Atopic Dermatitis Over Time

“…2DS4*001:01 and 2DL4*001:02 in the presence of C*04:01 and the KIR B haplotype 2DL4*001:02$2DS4*001:01$3DL2:002:01 also in the presence of C*04:01 is associated with decreased likelihood for AD remission (i.e., severe AD). This is likely consistent with the findings of both Mack et al and Min et al, who indicated that the activation of circulating NK cells appears to decrease AD symptoms (7,56). This is also consistent with a recent study by M€ obus et al, who showed that NK cell numbers were elevated in AD lesion and nonlesion skin and that NK cell activation by successful treatment results in clinical improvement (52,57).…”

“…A more recent study by Mack et al revealed that the number of circulating NK cells in adults with moderate to severe AD was significantly less than in a healthy control population (7). This was recently replicated (16,56). Mack et al further noticed a diminished number of circulating mature NK cells, whereas lesional AD skin was enriched for activated NK cells (7).…”

“…Mack et al further noticed a diminished number of circulating mature NK cells, whereas lesional AD skin was enriched for activated NK cells (7). Furthermore, a subset of circulating NK cells may be able to suppress Th2 cytokine-producing ILC2 cells that have been associated with AD, and transferring the human cells to an AD mouse model can suppress inflammatory skin responses in the mouse (56). Increased numbers of tissue-resident NK cell have been seen in both human AD lesions and mouse lesional skin samples (7,56).…”

“…Furthermore, a subset of circulating NK cells may be able to suppress Th2 cytokine-producing ILC2 cells that have been associated with AD, and transferring the human cells to an AD mouse model can suppress inflammatory skin responses in the mouse (56). Increased numbers of tissue-resident NK cell have been seen in both human AD lesions and mouse lesional skin samples (7,56). Although both tissue-resident and circulating NK cells exist, the tissue-resident NK cells are likely less cytotoxic (52).…”

Natural Killer Cells in Atopic Dermatitis Opening Doors to New Treatments

“…In details, they found that the majority of cutaneous ILCs between AD and normal human skin (NHS) belonged to the CRTH2 + subpopulation and these cells resided in the upper skin layers [59]. Instead, Min verified that the CD1d hi PD-L1 hi CD27 + regulatory NK cell subset could efficiently suppress AD via significantly inhibiting the numbers of ILC2s and Th2 cells, which collectively suggested the biofunction and association of TGF-β-producing NK cells with the severity of AD [60].…”