TLRs Mediate IFN-γ Production by Human Uterine NK Cells in Endometrium

Journal of Immunology - Tập 176 Số 10 - Trang 6219-6224 - 2006
Mikael Eriksson1, Sarah K. Meadows1, Satarupa Basu1, Teddy Mselle1, Charles R. Wira2, Charles L. Sentman1
1Department of Microbiology and Immunology and
2†Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756

Tóm tắt

Abstract

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-γ 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-γ upon stimulation with peptidoglycan or poly(I:C). However, purified uNK cells did not respond directly to TLR agonists, but IFN-γ 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-γ. These data also indicate that the uNK cells do not respond directly to TLR stimulation, but rather their production of IFN-γ is dependent upon interactions with other cells within EM.

Từ khóa


Tài liệu tham khảo

Tabibzadeh, S.. 1990. Proliferative activity of lymphoid cells in human endometrium throughout the menstrual cycle. J. Clin. Endocrinol. Metab. 70: 437-443.

Wira, C. R., J. V. Fahey, H. D. White, G. R. Yeaman, A. L. Givan, A. L. Howell. 2002. The mucosal immune system in the human female reproductive tract: influence of stage of the menstrual cycle and menopause on mucosal immunity in the uterus. S. Glasser, and J. Aplin, and L. Giudice, and S. Tabibzadeh, eds. Endometrium 371-404. Harwood Academic Publishers, Reading.

Spornitz, U. M.. 1992. The functional morphology of the human endometrium and decidua. Adv. Anat. Embryol. Cell Biol. 124: 1-99.

Yeaman, G. R., P. M. Guyre, M. W. Fanger, J. E. Collins, H. D. White, W. Rathbun, K. A. Orndorff, J. Gonzalez, J. E. Stern, C. R. Wira. 1997. Unique CD8+ T cell-rich lymphoid aggregates in human uterine endometrium. J. Leukocyte Biol. 61: 427-435.

Givan, A. L., H. D. White, J. E. Stern, E. Colby, E. J. Gosselin, P. M. Guyre, C. R. Wira. 1997. Flow cytometric analysis of leukocytes in the human female reproductive tract: comparison of fallopian tube, uterus, cervix, and vagina. Am. J. Reprod. Immunol. 38: 350-359.

Hunt, J. S.. 1994. Immunologically relevant cells in the uterus. Biol. Reprod. 50: 461-466.

King, A., V. Wellings, L. Gardner, Y. W. Loke. 1989. Immunocytochemical characterization of the unusual large granular lymphocytes in human endometrium throughout the menstrual cycle. Hum. Immunol. 24: 195-205.

Trinchieri, G.. 1989. Biology of natural killer cells. Adv. Immunol. 47: 187-376.

Robertson, M. J., J. Ritz. 1990. Biology and clinical relevance of human natural killer cells. Blood 76: 2421-2438.

Sedlmayr, P., L. Schallhammer, A. Hammer, M. Wilders-Truschnig, R. Wintersteiger, G. Dohr. 1996. Differential phenotypic properties of human peripheral blood CD56dim+ and CD56bright+ natural killer cell subpopulations. Int. Arch. Allergy Immunol. 110: 308-313.

King, A., P. P. Jokhi, T. D. Burrows, L. Gardner, A. M. Sharkey, Y. W. Loke. 1996. Functions of human decidual NK cells. Am. J. Reprod. Immunol. 35: 258-260.

Eriksson, M., S. K. Meadows, C. R. Wira, C. L. Sentman. 2004. Unique phenotype of human uterine NK cells and their regulation by endogenous TGF-β. J. Leukocyte Biol. 76: 667-675.

Schmidt, K. N., B. Leung, M. Kwong, K. A. Zarember, S. Satyal, T. A. Navas, F. Wang, P. J. Godowski. 2004. APC-independent activation of NK cells by the Toll-like receptor 3 agonist double-stranded RNA. J. Immunol. 172: 138-143.

Chalifour, A., P. Jeannin, J. F. Gauchat, A. Blaecke, M. Malissard, T. N′Guyen, N. Thieblemont, Y. Delneste. 2004. Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers α-defensin production. Blood 104: 1778-1783.

Sivori, S., M. Falco, M. Della Chiesa, S. Carlomagno, M. Vitale, L. Moretta, A. Moretta. 2004. CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumors and dendritic cells. Proc. Natl. Acad. Sci. USA 101: 10116-10121.

Hart, O. M., V. Athie-Morales, G. M. O’Connor, C. M. Gardiner. 2005. TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-γ production. J. Immunol. 175: 1636-1642.

Kamath, A. T., C. E. Sheasby, D. F. Tough. 2005. Dendritic cells and NK cells stimulate bystander T cell activation in response to TLR agonists through secretion of IFN-αβ and IFN-γ. J. Immunol. 174: 767-776.

Koopman, L. A., H. D. Kopcow, B. Rybalov, J. E. Boyson, J. S. Orange, F. Schatz, R. Masch, C. J. Lockwood, A. D. Schachter, P. J. Park, J. L. Strominger. 2003. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J. Exp. Med. 198: 1201-1212.

White, H. D., R. H. Prabhala, S. L. Humphrey, K. M. Crassi, J. M. Richardson, C. R. Wira. 2000. A method for the dispersal and characterization of leukocytes from the human female reproductive tract. Am. J. Reprod. Immunol. 44: 96-103.

Uronen-Hansson, H., J. Allen, M. Osman, G. Squires, N. Klein, R. E. Callard. 2004. Toll-like receptor 2 (TLR2) and TLR4 are present inside human dendritic cells, associated with microtubules and the Golgi apparatus but are not detectable on the cell surface: integrity of microtubules is required for interleukin-12 production in response to internalized bacteria. Immunology 111: 173-178.

Lidstrom, C., L. Matthiesen, G. Berg, S. Sharma, J. Ernerudh, C. Ekerfelt. 2003. Cytokine secretion patterns of NK cells and macrophages in early human pregnancy decidua and blood: implications for suppressor macrophages in decidua. Am. J. Reprod. Immunol. 50: 444-452.

Becker, I., N. Salaiza, M. Aguirre, J. Delgado, N. Carrillo-Carrasco, L. G. Kobeh, A. Ruiz, R. Cervantes, A. P. Torres, N. Cabrera, et al 2003. Leishmania lipophosphoglycan (LPG) activates NK cells through Toll-like receptor-2. Mol. Biochem. Parasitol. 130: 65-74.

Duan, X., M. Ackerly, E. Vivier, P. Anderson. 1994. Evidence for involvement of β-glucan-binding cell surface lectins in human natural killer cell function. Cell. Immunol. 157: 393-402.

Kitaya, K., J. Yasuda, I. Yagi, Y. Tada, S. Fushiki, H. Honjo. 2000. IL-15 expression at human endometrium and decidua. Biol. Reprod. 63: 683-687.

Pioli, P. A., E. Amiel, T. M. Schaefer, J. E. Connolly, C. R. Wira, P. M. Guyre. 2004. Differential expression of Toll-like receptors 2 and 4 in tissues of the human female reproductive tract. Infect. Immun. 72: 5799-5806.

Schaefer, T. M., J. V. Fahey, J. A. Wright, C. R. Wira. 2005. Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C). J. Immunol. 174: 992-1002.

Wang, J. P., E. A. Kurt-Jones, O. S. Shin, M. D. Manchak, M. J. Levin, R. W. Finberg. 2005. Varicella-zoster virus activates inflammatory cytokines in human monocytes and macrophages via Toll-like receptor 2. J. Virol. 79: 12658-12666.

Siren, J., J. Pirhonen, I. Julkunen, S. Matikainen. 2005. IFN-α regulates TLR-dependent gene expression of IFN-α, IFN-β, IL-28, and IL-29. J. Immunol. 174: 1932-1937.

Takeda, K., T. Kaisho, S. Akira. 2003. Toll-like receptors. Annu. Rev. Immunol. 21: 335-376.

Yuan, D.. 2004. Interactions between NK cells and B lymphocytes. Adv. Immunol. 84: 1-42.