Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-848d4c4894-xfwgj Total loading time: 0 Render date: 2024-07-04T12:13:11.221Z Has data issue: false hasContentIssue false

11 - Trophoblast and uterine mucosal leukocytes

from General discussion II

Published online by Cambridge University Press:  07 August 2009

By
Ashley Moffett
Edited by
Ashley Moffett ,
Charlie Loke  and
Anne McLaren
Ashley Moffett
Affiliation:
University of Cambridge, UK
Ashley Moffett
Affiliation:
University of Cambridge
Charlie Loke
Affiliation:
University of Cambridge
Anne McLaren
Affiliation:
Cancer Research, UK
Get access

Summary

Introduction

The mucosal lining of the uterus is transformed from endometrium in the non-pregnant state to the decidua of pregnancy. This transformation is induced under the influence of progesterone and is associated with leukocyte infiltration (Loke & King 1995, King 2000). In decidua, 70% of the infiltrating leukocytes are CD56bright natural killer (NK) cells together with some macrophages. Only small numbers of T cells are present (5%–15% of leukocytes) and B cells are virtually absent (King et al. 1989). Thus, at the site of trophoblast invasion in the first trimester, an influx of cells of the specific adaptive immune system does not occur so it seems unlikely that a maternal classical immune response to trophoblast is generated in the decidua. In contrast, there is an accumulation of innate immune cells, such as NK cells and macrophages at the implantation site. Recently, a population of dendritic cells (DCs) have been isolated and characterised from human decidua which have the phenotype of immature myeloid DCs (Gardner & Moffett 2003).

Uterine NK cells

The infiltration of uterine (u)NK cells is a part of the cyclical changes of the endometrium and it is clearly influenced by sex hormones, particularly progesterone. Recently, endometrial-derived interleukin (IL)15 and prolactin have been implicated in the proliferation and differentiation of these cells. Both of these hormones are produced by mucosal stromal cells and their production is up-regulated by progesterone as decidualisation occurs (Dunn et al. 2002, Gubbay et al. 2002).

Type
Chapter
Information
Biology and Pathology of Trophoblast , pp. 223 - 241
Publisher: Cambridge University Press
Print publication year: 2006

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Adams, E. J. & Parham, P. (2002). Species-specific evolution of MHC class I genes in the higher primates. Immunol. Rev., 183, 41–64.CrossRefGoogle Scholar
Akbari, O., DeKruyff, R. H. & Umetsu, D. T. (2001). Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat. Immun., 2, 725–31.CrossRefGoogle ScholarPubMed
Allan, D. S., Colonna, M., Lannier, L. L.et al. (1999). Tetrameric complexes of human histocompatibility leukocyte antigen (HLA-G)-G bind to peripheral blood myelomonocytic cells. J. Exp. Med., 189, 1149–56.CrossRefGoogle Scholar
Ashkar, A. A. & Croy, B. A. (2001). Functions of uterine natural killer cells are mediated by interferon-γ production during murine pregnancy. Semin. Immunol., 13, 235–41.CrossRefGoogle ScholarPubMed
Bancherau, J. & Steinman, R. M. (1998). Dendritic cells and the control of immunity. Nature, 392, 245–52.CrossRefGoogle Scholar
Barber, E. M. & Pollard, J. W. (2003). The uterine NK cell population requires IL-15 but these cells are not required for pregnancy nor the resolution of a Listeria monocytogenes infection. J. Immunol., 171, 37–46.CrossRefGoogle Scholar
Bell, S. J., Rigby, R., English, N.et al. (2001). Migration and maturation of human colonic dendritic cells. J. Immunol. 166, 4958–67.CrossRefGoogle ScholarPubMed
Braud, V. M., Allan, D. S., O'Callaghan, C. A.et al. (1998). HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature, 391, 795–9.CrossRefGoogle ScholarPubMed
Boyington, J. C., Brooks, A. G. & Sun, P. D. (2001). Structure of killer cell immunoglobulin-like receptors and their recognition of the class I MHC molecules. Immunol. Rev., 181, 62–5.CrossRefGoogle ScholarPubMed
Boyson, J. E., Erskine, R., Whitman, M. C.et al. (2002) Disulphide bond-mediated dimerization of HLA-G on the cell surface. Proc. Natl. Acad. Sci. U.S.A., 99, 16180–5.CrossRefGoogle ScholarPubMed
Bulmer, J. N., Pace, D. & Ritson, A. (1988). Immunoregulatory cells in human decidua: morphology, immunohistochemistry and function. Reprod. Nutr. Dev., 28, 1599–614.CrossRefGoogle ScholarPubMed
Burrows, T. D., King, A. & Loke, Y. W. (1993). Expression of adhesion molecules by human decidual large granular lymphocytes. Cell. Immunol., 147, 81–94.CrossRefGoogle ScholarPubMed
Burrows, T. D., King, A. & Loke, Y. W. (1994). Expression of adhesion molecules by endovascular trophoblast and decidual endothelial cells: implications for vascular invasion during implantation. Placenta, 15, 21–33.CrossRefGoogle ScholarPubMed
Chang, C. C., Ciubotariu, R., Manavalan, J. S.et al. (2002). Tolerization of dendritic cells by T cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat. Immun., 3, 237–43.CrossRefGoogle Scholar
Chantakru, S., Miller, C., Roach, L. E.et al. (2002). Contributions from self-renewal trafficking to the uterine NK-cell population of early pregnancy. J. Immunol., 168, 22–8.CrossRefGoogle ScholarPubMed
Critchley, H. O. D., Wang, H., Jones, R. L.et al. (1998). Morphological and functional features of endometrial decidualisation following long-term intrauterine levonorgestrel delivery. Hum. Reprod., 13, 1218–24.CrossRefGoogle Scholar
Dunn, C. L., Critchley, H. O. D. & Kelly, R. (2002). IL-15 regulation in human endometrial stromal cells. J. Clin. Endocrinol. Metab., 87, 1896–901.CrossRefGoogle ScholarPubMed
Fallon, P. G., Jolin, H. E., Smith, P.et al. (2002). IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. Immunity, 17, 7–17.CrossRefGoogle ScholarPubMed
Finger, E. B. & Bluestone, J. A. (2002). When ligand becomes receptor – tolerance via B7 signaling on DCs. Nat. Immun., 2, 1056–7.CrossRefGoogle Scholar
Finn, C. A. (1996). Why do women menstruate? Historical and evolutionary review. Eur. J. Obstet. Gynecol. Reprod. Biol., 70, 3–8.CrossRefGoogle ScholarPubMed
Finn, C. A. (1998). Menstruation: a nonadaptive consequence of uterine evolution. Q. Rev. Biol., 73, 163–73.CrossRefGoogle ScholarPubMed
Gardner, L. & Moffett, A. (2003). Dendritic cells in the human decidua. Biol. Reprod., 69, 1438–46.CrossRefGoogle ScholarPubMed
Georgiades, P., Ferguson-Smith, A. C. & Burton, G. J. (2002). Comparative developmental anatomy of the murine and human definitive placentae. Placenta, 23, 3–19.CrossRefGoogle ScholarPubMed
Goerdt, W. & Orfanos, C. E. (1999). Other functions, other genes: alternative activation of antigen-presenting cells. Immunity, 10, 137–42.CrossRefGoogle ScholarPubMed
Gonen-Gross, T., Achdout, H., Gazit, R.et al. (2003). Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function. J. Immunol., 171, 1343–51.CrossRefGoogle ScholarPubMed
Greenwood, J. D., Minnas, K., Santo, di J. P.et al. (2000). Ultrasound studies of implantation sites from mice deficient in uterine natural killer cells. Placenta, 120, 693–702.CrossRefGoogle Scholar
Griffin, M. D., Lutz, W., Phan, V. A.et al. (2001). Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent stage of immaturity in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A., 98, 6800–5.CrossRefGoogle Scholar
Gubbay, O., Critchley, H. O. D., King, A., Bowen, J. M. & Jabbour, H. N. (2002) Prolactin induces ERK phosphorylation in epithelial CD56+ natural killer cells of the human endometrium. J. Clin. Endocrinol. Metab., 87, 2329–35.CrossRefGoogle ScholarPubMed
Guimond, M.-J., Wang, B. & Croy, B. A. (1998). Engraftment of bone marrow from severe combined immunodeficient (SCID) mice reverses the reproductive deficit in natural killer cell-deficient tg∊26 mice. J. Exp. Med., 187, 217–23.CrossRefGoogle Scholar
Haedlicke, W., Ho, F. C. S., Chott, A.et al. (2000). Expression of CD94/NKG2A and killer immunoglobulin-like receptors in NK cells and a subset of extranodal cytotoxic T-cell lymphomas. Blood, 95, 3628–30.Google Scholar
Harizi, H., Juzan, M., Pitard, V., Moreau, J.-F. & Gualde, N. (2002). Cyclooxygenase-2-issued prostaglandin E2 enhances the production of endogenous IL-10, which down-regulates dendritic cell functions. J. Immunol., 168, 2255–63.CrossRefGoogle ScholarPubMed
Hart, D. N. (1997). Dendritic cells: unique leukocyte populations which control the primary immune response. Blood, 90, 3245–87.Google ScholarPubMed
Hiby, S. E., King, A., Sharkey, A. M. & Loke, Y. W. (1997). Human uterine cells have a similar repertoire of killer inhibitory and activatory receptors to those found in blood as demonstrated by RT-PCR and sequencing. Mol. Immunol., 34, 419–30.CrossRefGoogle ScholarPubMed
Huang, F.-P., Platt, N., Wykes, M.et al. (2000). A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J. Exp. Med., 191, 435–43.CrossRefGoogle Scholar
Jacobs, R., Hintzen, G., Kemper, A.et al. (2001). CD56bright cells differ in the KIR repertoire and cytotoxic features from CD56dim NK cells. Eur. J. Immunol., 31, 3121–3126.3.0.CO;2-4>CrossRefGoogle ScholarPubMed
Jokhi, P. P. (1994). Cytokines and their receptors in human placental implantation. Unpublished Ph. D. thesis, University of Cambridge.
Jokhi, P. P., Chumbley, G., Gardner, L., King, A. & Loke, Y. W. (1993). Expression of the colony stimulating factor-1 receptor (c-fms product) by cells at the human uteroplacental interface. Lab. Invest., 68, 308–20.Google ScholarPubMed
Jokhi, P. P., King, A., Jubinsky, P. & Loke, Y. W. (1994). Demonstration of the low affinity subunit of the granulocyte-macrophage colony-stimulating factor receptor (GM-CSF-Ra) on human trophoblast and uterine cells. J. Reprod. Immunol., 26, 147–64.CrossRefGoogle Scholar
Jonuleit, H., Schmitt, E., Schuler, G., Knop, J. & Enk, A. H. (2000). Induction of interleukin 10-producing, non-proliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J. Exp. Med., 192, 1213–22.CrossRefGoogle Scholar
Kennedy, T. G. (1988). Prostaglandins and other non-steroidal mediators at and immediately after implantation. In Beard, R. W. & Sharp, F., eds., Early Pregnancy Loss: Mechanisms and Treatment. London: RCOG Press, pp. 249–58.Google Scholar
Khakoo, S. I., Rajalingam, R., Shum, B. P.et al. (2000). Rapid evolution of NK-cell receptor systems demonstrated by comparison of chimpanzees and humans. Immunity, 12, 687–98.CrossRefGoogle ScholarPubMed
King, A. (2000). Uterine leucocytes and decidualisation. Hum. Reprod. Update, 6, 28–36.CrossRefGoogle Scholar
King, A., Wellings, V., Gardner, L. & Loke, Y. W. (1989). Immunocytochemical characterisation of the unusual large granular lymphocytes in human endometrium throughout the menstrual cycle. Hum. Immunol., 24, 195–205.CrossRefGoogle Scholar
King, A., Gardner, L. & Loke, Y. W. (1996). Evaluation of oestrogen and progesterone receptor expression in uterine mucosal lymphocytes. Hum. Reprod., 11, 1079–82.CrossRefGoogle ScholarPubMed
King, A., Allan, D. S. J., Joseph, S.et al. (2000a). HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells. Eur. J. Immunol., 30, 1623–31.3.0.CO;2-M>CrossRefGoogle Scholar
King, A., Burrows, T. D., Hiby, S. E.et al. (2000b). Surface expression of HLA-C antigen by human extravillous trophoblast. Placenta, 21, 376–87.CrossRefGoogle Scholar
Koopman, L. A., Kopcow, H. D., Rybalov, B.et al. (2003). Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J. Exp. Med., 198, 1201–12.CrossRefGoogle ScholarPubMed
Kruse, A., Martens, N., Gemekom, U., Hallmann, R. & Butcher, E. C. (2002). Alterations in the expression of homing-associated molecules at the maternal/fetal interface during the course of pregnancy. Biol. Reprod., 66, 333–45.CrossRefGoogle ScholarPubMed
Lanier, L. L. (1999). Natural killer cells fertile with receptors for HLA-G?Proc. Natl. Acad. Sci. U.S.A., 96, 5343–5.CrossRefGoogle ScholarPubMed
Lee, N., Llano, M., Carretero, M.et al. (1998). HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc. Natl. Acad. Sci. U.S.A., 95, 5199–204.CrossRefGoogle ScholarPubMed
Li, X. F., Charnock-Jones, S., Zhang, E.et al. (2001). Angiogenic growth factor mRNAs in uterine natural killer cells. J. Clin. Endocrinol. Metab., 86, 1823–34.Google ScholarPubMed
Liang, S., Baibakov, B. & Horuzsko, A. (2002). HLA-G inhibits the functions of murine dendritic cells via the PIR-B immune inhibitory receptor. Eur. J. Immunol., 32, 2418–26.3.0.CO;2-L>CrossRefGoogle ScholarPubMed
Liu, C.-C. & Young, J. D. E. (2001). Uterine natural killer cells in the pregnant uterus. Adv. Immunol., 79, 297–329.CrossRefGoogle ScholarPubMed
Liu, Y.-J., Kanzler, H., Souvelis, V. & Gilliet, M. (2001). Dendritic cell lineage, plasticity and cross-regulation. Nat. Immun., 2, 585–9.CrossRefGoogle ScholarPubMed
Llano, M., Lee, N., Navarro, F.et al. (1998). HLA-E bound peptides influence recognition by inhibitory and triggering CD94/NKG2 receptors: preferential response to an HLA-G derived nonamer. Eur. J. Immunol., 28, 2854–63.3.0.CO;2-W>CrossRefGoogle Scholar
Loke, Y. W. & King, A. (1995). Human Implantation: Cell Biology and Immunology. Cambridge: Cambridge University Press.Google Scholar
Loke, Y. W. & King, A. (1996). Immunology of human implantation: an evolutionary perspective. Hum. Reprod., 11, 283–6.CrossRefGoogle Scholar
Loke, Y. W., King, A., Burrows, T.et al. (1997). Evaluation of trophoblast HLA-G antigen with a specific monoclonal antibody. Tissue Antigens, 50, 135–46.CrossRefGoogle ScholarPubMed
Long, E. O., Barber, D. F., Burshtyn, D. N.et al. (2001). Inhibition of natural killer cell activation signals by killer cell immunoglobulin-like receptors (CD158). Immunol. Rev., 181, 223–33.CrossRefGoogle Scholar
Masler, I. A. (1988). The progestational endometrium. Semin. Reprod. Endocrinol., 6, 115–28.CrossRefGoogle Scholar
Massi, D., Susini, T., Paglierani, M., Salvadori, A. & Giannini, A. (1995). Pregnancy-associated ectopic decidua. Acta Obstet. Gynecol. Scand., 74, 568–71.CrossRefGoogle ScholarPubMed
McMaster, M., Zhou, Y., Shorter, S.et al. (1998). HLA-G isoforms produced by placental cytotrophoblasts and found in amniotic fluid are due to unusual glycosylation. J. Immunol., 160, 5992–8.Google ScholarPubMed
Mellor, A. L. & Munn, D. H. (1999). Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation?Immunol. Today, 20, 469–73.CrossRefGoogle ScholarPubMed
Moffett-King, A. (2002). Natural killer cells and pregnancy. Nat. Rev. Immunol., 2, 656–63.CrossRefGoogle Scholar
Miyazaki, S., Tsuda, H., Sakai, M.et al. (2003). Predominance of Th2-promoting dendritic cells in early human pregnancyJ. Leukocyte Biol., 74, 514–22.CrossRefGoogle ScholarPubMed
Nagler-Anderson, C. (2001). Man the barrier! Strategic defences in the intestinal mucosa. Nat. Rev. Immunol., 1, 59–67.CrossRefGoogle ScholarPubMed
Navarro, F., Llano, M., Bellon, T.et al. (1999). The ILT2(LIR1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells. Eur. J. Immunol., 29, 277–83.3.0.CO;2-4>CrossRefGoogle ScholarPubMed
Ponte, M., Cantoni, C., Biassoni, R.et al. (1999). Inhibitory receptors sensing HLA-G1 molecules in pregnancy: decidua-associated natural killer cells express LIR-1 and CD94/NKG2A and acquire p49, an HLA-G1-specific receptor. Proc. Natl. Acad. Sci. U.S.A., 96, 5674–9.CrossRefGoogle ScholarPubMed
Rajagopalan, S. & Long, E. O. (1999). A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. J. Exp. Med., 189, 1093–100.CrossRefGoogle ScholarPubMed
Rajalingam, R., Hong, M., Adams, E. J.et al. (2001). Short KIR haplotypes in pygmy chimpanzee (bonobo) resemble the conserved framework of diverse human KIR haplotypes. J. Exp. Med., 193, 135–46.CrossRefGoogle ScholarPubMed
Rajalingam, R., Parham, P. & Abi-Rached, L. (2004). Domain shuffling has been the main mechanism forming new hominoid killer cell Ig-like receptors. J. Immunol., 172, 356–69.CrossRefGoogle ScholarPubMed
Rolph, G. J. (2002). Is maturation required for Langerhans cell migration?J. Exp. Med., 196, 413–16.Google Scholar
Rossant, J. & Cross, J. C. (2001). Placental development: lessons from mouse mutants. Nat. Rev. Genet., 2, 538–48.CrossRefGoogle ScholarPubMed
Roth, I. & Fisher, S. J. (1999). IL-10 is an autocrine inhibitor of human placental cytotrophoblast MMP-9 production and invasion. Dev. Biol., 205, 194–204.CrossRefGoogle ScholarPubMed
Sharkey, A. M., Charnock-Jones, D. S., Brown, K. D. & Smith, S. K. (1992). Expression of messenger RNA for kit-ligand in human placenta: localization by in situ hybridisation and identification of alternatively spliced variants. Mol. Endocrinol., 6, 1235–41.Google Scholar
Sharkey, A. M., Charnock-Jones, D. S., Boocock, C. A., Brown, K. D. & Smith, S. K. (1993). Expression of mRNA for vascular endothelial growth factor in human placenta. J. Reprod. Fertil., 99, 609–15.CrossRefGoogle ScholarPubMed
Sharkey, A. M., Jokhi, P. P., King, A.et al. (1994). Expression of c-kit and kit ligand at the human materno-fetal interface. Cytokine, 6, 195–205.CrossRefGoogle Scholar
Shiroishi, M., Tsumoto, K., Amano, K.et al. (2003). Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proc. Natl. Acad. Sci. U.S.A., 100, 8856–61.CrossRefGoogle ScholarPubMed
Spornitz, U. M. (1992). The functional morphology of the human endometrium and decidua. Adv. Anat. Embryol. Cell Biol., 124, 1–99.CrossRefGoogle ScholarPubMed
Steinman, R. M. & Nussenzweig, M. C. (2002). Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc. Natl. Acad. Sci. U.S.A., 99, 351–8.CrossRefGoogle ScholarPubMed
Steven, D. H. (1975). Comparative Placentation. Essays in Structure and Function. London: Academic Press.Google Scholar
Szabolcs, P., Avigan, D., Gezelter, S.et al. (1996). Dendritic cells and macrophages can mature independently from a human bone marrow-derived post-colony-forming unit intermediate. Blood, 87, 4520–30.Google ScholarPubMed
Trundley, A. & Moffett, A. (2004). Human uterine leukocytes and pregnancy. Tissue Antigens, 63, 1–12.CrossRefGoogle Scholar
Turville, S. G., Cameron, P. U., Handley, A.et al. (2002). Diversity of receptors binding HIV on dendritic cell subsets. Nat. Immun., 3, 975–83.CrossRefGoogle ScholarPubMed
Uhrberg, M., Valiante, N. M., Shun, B. P.et al. (1997). Human diversity in killer cell inhibitory genes. Immunity, 7, 753–63.CrossRefGoogle Scholar
Vales-Gomez, M., Reburn, H. T., Erskine, R. A., Lopez-Botet, M. & Strominger, J. L. (1999). Kinetics and peptide dependency of the binding of the inhibitory NK receptor CD94/NKG2-A and the activating receptor CD94/NKG2-C to HLA-E. EMBO J., 18, 4250–60.CrossRefGoogle ScholarPubMed
Verma, S., King, A. & Loke, Y. W. (1997). Expression of killer-cell inhibitory receptors (KIR) on human uterine NK cells. Eur. J. Immunol., 27, 979–83.CrossRefGoogle Scholar
Vilches, C. & Parham, P. (2002). KIR: diverse, rapidly evolving receptors of innate adaptive immunity. Annu. Rev. Immunol., 20, 217–51.CrossRefGoogle Scholar
Wilson, M., Torkar, M., Haude, A.et al. (2000). Plasticity in the organization and sequences of human KIR/ILT gene families. Proc. Natl. Acad. Sci. U.S.A., 97, 4778–83.CrossRefGoogle ScholarPubMed
Zehnder, D., Evans, K. N., Kilby, M. D.et al. (2002). The ontogeny of 25-hydroxyvitamin D(3) 1alpha-hydroxylase expression in human placenta decidua. Am. J. Pathol., 161, 105–14.CrossRefGoogle Scholar
Zivogel, L. (2002). Dendritic and natural killer cells cooperate in the control/switch of innate immunity. J. Exp. Med., 195, F9–14.CrossRefGoogle Scholar

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×