Subject(s)
Antibodies, Monoclonal/therapeutic use , Drug Design , Immunoconjugates/therapeutic use , Ado-Trastuzumab Emtansine , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Brentuximab Vedotin , Drug Industry/trends , Humans , Immunoconjugates/administration & dosage , Maytansine/administration & dosage , Maytansine/analogs & derivatives , Maytansine/therapeutic use , Molecular Targeted Therapy , Technology, Pharmaceutical/methods , TrastuzumabABSTRACT
PROBLEM: The initiation of an immune response often involves the cooperation of various innate immune cells. In the human endometrium, uterine natural killer (uNK) cells and uterine macrophages are present in significant numbers and in close proximity, yet how they cooperatively respond to infectious challenge is poorly understood. METHOD OF STUDY: Primary autologous uNK cells and macrophages were co-cultured to determine functional interactions after stimulation with pathogen-associated molecular patterns. RESULTS: After stimulation by polyI:C, human uNK cells interact with autologous uterine macrophages and produce interferon-gamma in an NKG2D-dependent manner. Stimulated primary uterine macrophages up-regulated the expression of MHC Class I chain-related protein A (MICA), but expression of the cognate receptor NKG2D remained unchanged on uNK cells, even in the presence of cytokines. CONCLUSION: This study demonstrates that the NKG2D-MICA interaction is an important molecular mechanism that is involved in the innate immune response to microbial signals in the human uterine endometrium.
Subject(s)
Killer Cells, Natural/immunology , Macrophages/immunology , NK Cell Lectin-Like Receptor Subfamily K/immunology , Uterus/immunology , Adult , CD56 Antigen/metabolism , Female , Humans , Interferon-gamma/biosynthesis , Killer Cells, Natural/drug effects , Lipopolysaccharide Receptors/metabolism , Macrophages/metabolism , Middle Aged , Poly I-C/pharmacology , Toll-Like Receptor 3/immunology , Toll-Like Receptor 3/metabolism , Up-Regulation , Uterus/drug effects , Uterus/metabolismABSTRACT
The human endometrium undergoes cyclical changes regulated by sex hormones. Evidence suggests that sex hormones regulate NK cell recruitment into the uterus in large numbers. NKG2D is an activating receptor expressed on human NK cells, gammadelta and CD8 T cells. NKG2D ligands are known to be sensors of cellular "stress". In this study, we investigated whether sex hormones directly regulate expression of NKG2D ligands in the human uterus. Estradiol increased MICA expression on uterine epithelial cells; regulation was estrogen receptor-dependent. Real-time PCR analysis showed that NKG2D ligands MICA and MICB were expressed in the human endometrium. MICA protein was detected primarily on epithelial cells, and greater expression was observed in immunohistochemical analysis of tissues from patients in the secretory phase of the menstrual cycle. Thus, estrogens regulate expression of MICA. These data suggest hormonal regulation of innate immunity and NKG2D-mediated recognition in other tissues and diseases where estrogen may be involved.
Subject(s)
Endometrium/immunology , Estradiol/pharmacology , Gene Expression Regulation/drug effects , Histocompatibility Antigens Class I/genetics , Cell Line, Tumor , Female , GPI-Linked Proteins , Histocompatibility Antigens Class I/analysis , Histocompatibility Antigens Class I/physiology , Humans , Intercellular Signaling Peptides and Proteins/analysis , RNA, Messenger/analysisABSTRACT
The human endometrium (EM) contains macrophages, NK cells, T cells, B cells, and neutrophils in contact with a variety of stromal and epithelial cells. The interplay between these different cell types and their roles in defense against pathogen invasion in this specialized tissue are important for controlling infection and reproduction. TLRs are a family of receptors able to recognize conserved pathogen-associated molecular patterns. In this study, we determined the expression of TLRs on uterine NK (uNK) cells from the human EM and the extent to which uNK cells responded to TLR agonist stimulation. uNK cells expressed TLRs 2, 3, and 4, and produced IFN-gamma when total human endometrial cells were stimulated with agonists to TLR2 or TLR3 (peptidoglycan or poly(I:C), respectively). Activated uNK cell clones produced IFN-gamma upon stimulation with peptidoglycan or poly(I:C). However, purified uNK cells did not respond directly to TLR agonists, but IFN-gamma was produced by uNK cells in response to TLR stimulation when cocultured with APCs. These data indicate that uNK cells express TLRs and that they can respond to TLR agonists within EM by producing IFN-gamma. These data also indicate that the uNK cells do not respond directly to TLR stimulation, but rather their production of IFN-gamma is dependent upon interactions with other cells within EM.