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Protective role of regulatory decidual γδ T cells in pregnancy
Clinical Immunology (2011) 141, 236–239
available at www.sciencedirect.com
Clinical Immunology www.elsevier.com/locate/yclim
EDITORIAL
Protective role of regulatory decidual γδ T cells in pregnancy Mammalian pregnancy represents a unique physiological challenge to an organism naturally reactive to ‘foreign bodies’. The pregnant female routinely fosters the development of a fetus that expresses paternally-derived alloantigens, yet she does not develop an immune response as she would to an allogeneic solid organ transplant. Indeed, much of the research conducted in the fifty or so years on this immunological paradox of pregnancy has been guided by the conceptual framework that a successful pregnancy must depend on the evasion by the fetus of allorecognition mediated by adaptive arm of the maternal immune system. However, developments in recent years have revealed that this view may have been overly simplistic. In this issue, Fan et al., add to the accumulating evidence indicating that the localized maternal immune response may actually facilitate placental development [1]. The placental immunological environment is unusual in a number of ways. For example, the embryo-derived trophoblasts responsible for ‘invading’ the maternal uterine wall and helping to establish implantation lack many of the polymorphic classical MHC class 1 molecules (Fig. 1). Instead, trophoblasts express non-polymorphic non-classical MHC class I molecules such as HLA-G [2] and HLA-E ([3] King) that can be recognized by a number of decidual leukocyte populations [4], and the MHC class I-like molecule CD1d, recognized by natural killer T cells (‘NKT’) cells [5]. The establishment of the mammalian placenta a highly dynamic and invasive process that has, at its core, a fetusderived cell called the trophoblast [6]. This trophectodermderived cell lineage gives rise to both the syncytiotrophoblast, the critical hormone-producing outermost layer of the blastocyst, and the invasive extravillous trophoblasts, so named because of their ability to migrate from anchoring chorionic villi. Extravillous trophoblasts migrate throughout the decidua, reshaping and remodeling maternal tissue as they secrete a variety of matrix metalloproteinases, until they reach their ultimate destination which is the maternal spiral arterioles (Fig. 1). There, the extravillous trophoblasts invade and replace the endothelium of the maternal blood vessels, transforming them into relatively low-resistance conduits that promote 1521-6616/$ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2011.09.004
proper perfusion of the placenta. It is generally agreed upon that impaired trophoblast invasion and remodeling of the maternal tissues underlies disorders of pregnancy such as preeclampsia and intra-uterine growth retardation [6]. Throughout their migration through the decidua, trophoblasts are in intimate contact with maternal decidual leukocytes, which comprise anywhere from 10 to 25% of all cells in the decidua [7]. In general, innate-like immune cells are enriched in epithelial tissues such as lung, skin, intestine, and liver, and in this, the decidua is no different. Although CD4 +, CD8 +, and regulatory T cells are present, the maternal decidual leukocyte population early in gestation is characterized largely by cells of the innate arm. Macrophages are abundant, as are CD16 −CD56 bright decidual NK cells, which can comprise up to 70% of the decidual lymphocyte population [7], and NKT cells [5]. The report by Fan et al. [1] now adds to previous studies showing that a sizeable fraction of the decidual CD3 + T cell population is dominated by the innate-like gamma delta (γδ) T subset. In humans and rodents, classical αβ T cells outnumber γδ T cells in most lymphoid organs by more than 10:1 and γδ T cells represent ~1–10% of total PBMC T cells [8]. In ruminants, however, the reverse is true [8]. Unlike classical αβ T cells, the limited TCR repertoire of γδ T cells recognizes a range of non-peptidic antigens that are not MHC-restricted. γδ T cell antigens began to be identified in the 1990s [8,9]. Vδ1+ T cells can recognize the stress-inducible MHC-related molecules MICA/B and other ligands [8,9]. A major γδ T cell subset in peripheral blood mononuclear cells (PBMC) of healthy humans are Vγ9Vδ2+ T cells. The Vγ9Vδ2+ T cell TCR recognizes natural phosphonates [isopentenyl pyrophosphate (IPP)] and synthetics (e.g. BrHPP/Bromohydrin pyrophosphate and HMBPP/Hydroxy–methyl–butenyl–pyrophosphate) phosphoantigens [8,9]. Such phosphoantigens can be overexpressed by tumor cells, possibly due to metabolic stress, which can activate Vγ9Vδ2+ T cell cytotoxicity [8,9]. Hence Vγ9Vδ2+ T cells also have anti-tumor potential. Zoledronate induces the formation of metabolites like isopentyl phosphates, which can be recognized by γδ T cells, specifically
Editorial
237
Figure 1 Schematic of the human maternal-fetal interface. On the right is a close-up view of a single chorionic villous. Fetus-derived trophoblasts give rise to both the syncytiotrophoblast, the hormone-producing outermost layer of the chorionic villi, and the invasive extravillous trophoblasts (EVTBs), so named because of their ability to migrate from anchoring chorionic villi. EVTBs migrate through the decidua, eventually invading the maternal spiral arterioles, transforming them into relatively low-resistance blood vessels that promote proper perfusion of the placenta.
the Vγ9Vδ2+ subset [10,11]. This is a significant aspect, given that zoledronate is an approved drug for the prevention of bone resorption due to local metastases from a variety of cancers. There has been a recent flurry of papers describing the effects of zoledronate on γδ T cells, including clinical trials of zoledronate used directly in vivo with IL-2 or for ex vivo expansion of γδ T cells for cell therapy [11–13]. In contrast to blood, decidual γδ T cells can have more of other subsets. Both Vδ1+ and Vγ9Vδ2+ T cells with regulatory phenotype are found in decidua [14–18]. A cloning study showed that there maybe microanatomical heterogeneity, in that decidua parietalis has b50% Vγ9Vδ2+ T cells and more than 50% are Vδ1+ T cells (b 15% of PBMC γδ T cells). Decidual basalis γδ T cells were ~95% Vγ9Vδ2+ T cells [19], a higher proportion than in blood. In a histochemical study, γδ T cells were scattered in the endometrial/decidual stroma [20]. Of course, these fractions may vary during pregnancy. What then is the potential function of decidual γδ T cells? Fan et al. [1] examine γδ T cells in the human decidua, finding that they are predominantly CD4–CD8- ‘double negative’ (DN) T cells with overall regulatory (Treg) phenotype. Extending earlier reports [14–18], they find that these cells are highly biased toward IL-10 and TGF-β1 production. Also present are IFN-γ and TNF-α-producing γδ T cells, but these comprise only a minor population. Although not investigated by Fan et al., it may be of interest to determine whether the γδ T cell population is comprised of multiple subsets (i.e., an IFN-γ/TNF-producing subset and an IL-10/ TGF-β1-producing subset) or whether a fraction of the decidual γδ T cells can produce simultaneously Th1-like and Treg-type cytokines, similar to NKT cells. Importantly, Fan
et al., extend these findings by demonstrating that coculture of decidual γδ T cells with trophoblasts promotes trophoblast proliferation and attenuates trophoblast apoptosis [1]. They go on to demonstrate that these functions are mediated in large part by IL-10. Consistent with this finding is their demonstration that IL-10 produced by γδ T cells promotes trophoblast invasion through extracellular matrix in vitro [1]. The report by Fan et al., provides further support for the notion that the recognition of fetal cells by the maternal immune system need not have only negative consequences. This is consistent with reports that decidual NK cells release IL-8 and IP-10 chemokines that act on trophoblast cells, promoting their invasion into the endometrium [21,22]. Decidual NK cells also produce proangiogenic VEGF and PLGF, which can induce endothelial activation and aid in the establishment of placental vasculature [21]. In addition, ligands for the decidual NK cell activating receptors NKp44 and NKp30 can be expressed by maternal stromal cells (both ligands) and by trophoblast cells (NKp44) [21]. Indeed, given that decidual NK cells can also produce IL-10 [23], one wonders to what extent do the functions of decidual NK and γδ T cells overlap. Or, is it the case that the overall inflammatory environment in which the decidual NK cells are immersed is balanced by the more regulatory ‘flavor’ of decidual γδ T cells? There is another possibility too, given recent results that IL-10 appears to protect activated NK cells from apoptosis [24], which may allow NK cells to perform their role in decidua too. Clearly, despite potential modest human–animal differences, direct in vivo model experiments are warranted for definitive testing of the hypothesis proposed by Fan [1], that
238 IL-10 produced by γδ T cells contributes to trophoblast invasion and thereby successful pregnancy. However, the regulatory phenotype of human decidual γδ T cells clearly supports their potential to contribute toward maintenance of a noninflammatory micro-environment. Further results have linked failure of this regulatory activity of human decidual γδ T cells to pathological outcomes in pregnancy [18,25,26]. In general, results in mouse [27–32] and large animal models [33,34] also support the emerging protective role of decidual γδ T cells.
References [1] D.-X. Fan, J. Duan, M.-Q. Li, B. Xu, D.-J. Li, L.-P. Jin, The decidual gamma-delta T cells up-regulate the biological functions of trophoblasts via IL-10 secretion in early human pregnancy, Clin. Immunol. 141 (2011) 284–292. [2] S. Kovats, et al., A class I antigen, HLA-G, expressed in human trophoblasts, Science 248 (4952) (1990) 220–223. [3] A. King, et al., HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells, Eur. J. Immunol. 30 (6) (2000) 1623–1631. [4] D.S. Allan, A.J. McMichael, V.M. Braud, The ILT family of leukocyte receptors, Immunobiology 202 (2000) 34–41. [5] J.E. Boyson, et al., CD1d and invariant NKT cells at the human maternal–fetal interface, Proc. Natl. Acad. Sci. U. S. A. 99 (21) (2002) 13741–13746. [6] E.R. Norwitz, D.J. Schust, S.J. Fisher, Implantation and the survival of early pregnancy, N. Engl. J. Med. 345 (2001) 1400–1408. [7] A.L. Mellor, D.H. Munn, Immunology at the maternal–fetal interface: lessons for T cell tolerance and suppression, Annu. Rev. Immunol. 18 (2000) 367–391. [8] A.C. Hayday, Gamma-delta T cells and the lymphoid stresssurveillance response, Immunity 31 (2009) 184–196. [9] R.L. O'Brien, M. Lahn, W.K. Born, S.A. Huber, T cell receptor and function cosegregate in gamma-delta T cell subsets, Chem. Immunol. 79 (2001) 1–28 Review. PubMed PMID: 11478152. [10] F. Dieli, N. Gebbia, F. Poccia, N. Caccamo, C. Montesano, F. Fulfaro, C. Arcara, M.R. Valerio, S. Meraviglia, C. Di Sano, G. Sireci, A. Salerno, Induction of gammadelta T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo, Blood 102 (6) (Sep 15 2003) 2310–2311 PubMed PMID: 12959943. [11] S.R. Mattarollo, T. Kenna, M. Nieda, A.J. Nicol, Chemotherapy and zoledronate sensitize solid tumour cells to Vgamma9Vdelta2 T cell cytotoxicity, Cancer Immunol. Immunother. 56 (8) (Aug 2007) 1285–1297 Epub 2007 Jan 31. PubMed PMID: 17265022. [12] F. Dieli, D. Vermijlen, F. Fulfaro, N. Caccamo, S. Meraviglia, G. Cicero, A. Roberts, S. Buccheri, M. D'Asaro, N. Gebbia, A. Salerno, M. Eberl, A.C. Hayday, Targeting human {gamma} delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer, Cancer Res. 67 (15) (Aug 1 2007) 7450–7457 PubMed PMID: 17671215. [13] N. Caccamo, S. Meraviglia, F. Scarpa, C. La Mendola, D. Santini, C.T. Bonanno, G. Misiano, F. Dieli, A. Salerno, Aminobisphosphonate-activated gammadelta T cells in immunotherapy of cancer: doubts no more, Expert Opin. Biol. Ther. 8 (7) (Jul 2008) 875–883 Review. PubMed PMID: 18549319. [14] L. Mincheva-Nilsson, S. Hammarstrom, M.L. Hammarstrom, Human decidual leukocytes from early pregnancy contain high numbers of gamma delta+ cells and show selective down-regulation of alloreactivity, J. Immunol. 149 (6) (1992) 2203–2211. [15] J. Szekeres-Bartho, A. Barakonyi, E. Miko, B. Polgar, T. Palkovics, The role of gamma/delta T cells in the feto–maternal relationship, Semin. Immunol. 13 (4) (Aug 2001) 229–233 Review. PubMed PMID: 11437630.
EDITORIAL [16] A. Barakonyi, K.T. Kovacs, E. Miko, L. Szereday, P. Varga, J. Szekeres-Bartho, Recognition of nonclassical HLA class I antigens by gamma delta T cells during pregnancy, J. Immunol. 168 (6) (Mar 15 2002) 2683–2688 PubMed PMID: 11884433. [17] O. Nagaeva, L. Jonsson, L. Mincheva-Nilsson, Dominant IL-10 and TGF-beta mRNA expression in gammadeltaT cells of human early pregnancy decidua suggests immunoregulatory potential, Am. J. Reprod. Immunol. 48 (1) (2002) 9–17. [18] R. Giacomelli, P. Cipriani, A. Fulminis, J.L. Nelson, M. MatucciCerinic, Gamma/delta T cells in placenta and skin: their different functions may support the paradigm of microchimerism in systemic sclerosis, Clin. Exp. Rheumatol. 22 (3 Suppl 33) (Jan–Feb 2004) S28–S30 Review. PubMed PMID: 15344594. [19] S.E. Christmas, R. Brew, G. Deniz, J.J. Taylor, T-cell receptor heterogeneity of gamma delta T-cell clones from human female reproductive tissues, Immunology 78 (3) (Mar 1993) 436–443 PubMed PMID: 8386698; PubMed Central PMCID: PMC1421841. [20] H. Haller, O. Radillo, D. Rukavina, F. Tedesco, G. Candussi, O. Petrović, L. Randić, An immunohistochemical study of leucocytes in human endometrium, first and third trimester basal decidua, J. Reprod. Immunol. 23 (1) (Jan 1993) 41–49 PubMed PMID: 8429523. [21] J. Hanna, et al., Decidual NK cells regulate key developmental processes at the human fetal–maternal interface, Nat. Med. 12 (9) (2006) 1065–1074. [22] P. Le Bouteiller, J. Tabiasco, Killers become builders during pregnancy, Nat. Med. 12 (2006) 991–992. doi:10.1038/ nm0906-991. [23] P. Vigano, et al., Interleukin-10 is produced by human uterine natural killer cells but does not affect their production of interferon-gamma, Mol. Hum. Reprod. 7 (10) (2001) 971–977. [24] M.A. Stacey, M. Marsden, E.C. Wang, G.W. Wilkinson, I.R. Humphreys, IL-10 restricts activation-induced death of NK cells during acute murine cytomegalovirus infection, J. Immunol. 187 (6) (Sep 15 2011) 2944–2952 Epub 2011 Aug 17. PubMed PMID: 21849677. [25] L. Szereday, A. Barakonyi, E. Miko, P. Varga, J. SzekeresBartho, Gamma/deltaT-cell subsets, NKG2A expression and apoptosis of Vdelta2+ T cells in pregnant women with or without risk of premature pregnancy termination, Am. J. Reprod. Immunol. 50 (6) (Dec 2003) 490–496 PubMed PMID: 14750557. [26] L. Rieger, S. Segerer, T. Bernar, M. Kapp, M. Majic, A.K. Morr, J. Dietl, U. Kummerer, Specific subsets of immune cells in human decidua differ between normal pregnancy and preeclampsia — a prospective observational study, Reprod. Biol. Endocrinol. 7 (Nov 23 2009) 132 PubMed PMID: 19930648; PubMed Central PMCID: PMC2789084. [27] K. Heyborne, Y.X. Fu, A. Nelson, A. Farr, R. O'Brien, W. Born, Recognition of trophoblasts by gamma delta T cells, J. Immunol. 153 (7) (Oct 1 1994) 2918–2926 PubMed PMID: 8089477. [28] T. Suzuki, K. Hiromatsu, Y. Ando, T. Okamoto, Y. Tomoda, Y. Yoshikai, Regulatory role of gamma delta T cells in uterine intraepithelial lymphocytes in maternal antifetal immune response, J. Immunol. 154 (9) (May 1 1995) 4476–4484 PubMed PMID: 7722304. [29] P.C. Arck, D.A. Ferrick, D. Steele-Norwood, K. Croitoru, D.A. Clark, Regulation of abortion by gamma delta T cells, Am. J. Reprod. Immunol. 37 (1) (Jan 1997) 87–93 PubMed PMID: 9138458. [30] P.C. Arck, D.A. Ferrick, D. Steele-Norwood, P.J. Egan, K. Croitoru, S.R. Carding, J. Dietl, D.A. Clark, Murine T cell determination of pregnancy outcome, Cell. Immunol. 196 (2) (Sep 15 1999) 71–79 PubMed PMID: 10527558. [31] D.A. Clark, K. Croitoru, TH1/TH2,3 imbalance due to cytokineproducing NK, gammadelta T and NK-gammadelta T cells in murine pregnancy decidua in success or failure of pregnancy, Am. J. Reprod. Immunol. 45 (5) (May 2001) 257–265 PubMed PMID: 11432400.
Editorial [32] W.K. Born, Z. Yin, Y.S. Hahn, D. Sun, R.L. O'Brien, Analysis of gamma delta T cell functions in the mouse, J. Immunol. 184 (8) (Apr 15 2010) 4055–4061 Review. PubMed PMID: 20368285. [33] E. Meeusen, A. Fox, M. Brandon, C.S. Lee, Activation of uterine intraepithelial gamma delta T cell receptor-positive lymphocytes during pregnancy, Eur. J. Immunol. 23 (5) (May 1993) 1112–1117 PubMed PMID: 8477805. [34] E.N. Meeusen, R.J. Bischof, C.S. Lee, Comparative T-cell responses during pregnancy in large animals and humans, Am. J. Reprod. Immunol. 46 (2) (Aug 2001) 169–179 Review. PubMed PMID: 11506082.
239
Mark A. Exley Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA Corresponding author. Fax: + 1 617 667 0610. E-mail address: [email protected]. Jonathan E. Boyson Dept. of Surgery, University of Vermont College of Medicine, Burlington, VT, USA
available at www.sciencedirect.com
Clinical Immunology www.elsevier.com/locate/yclim
EDITORIAL
Protective role of regulatory decidual γδ T cells in pregnancy Mammalian pregnancy represents a unique physiological challenge to an organism naturally reactive to ‘foreign bodies’. The pregnant female routinely fosters the development of a fetus that expresses paternally-derived alloantigens, yet she does not develop an immune response as she would to an allogeneic solid organ transplant. Indeed, much of the research conducted in the fifty or so years on this immunological paradox of pregnancy has been guided by the conceptual framework that a successful pregnancy must depend on the evasion by the fetus of allorecognition mediated by adaptive arm of the maternal immune system. However, developments in recent years have revealed that this view may have been overly simplistic. In this issue, Fan et al., add to the accumulating evidence indicating that the localized maternal immune response may actually facilitate placental development [1]. The placental immunological environment is unusual in a number of ways. For example, the embryo-derived trophoblasts responsible for ‘invading’ the maternal uterine wall and helping to establish implantation lack many of the polymorphic classical MHC class 1 molecules (Fig. 1). Instead, trophoblasts express non-polymorphic non-classical MHC class I molecules such as HLA-G [2] and HLA-E ([3] King) that can be recognized by a number of decidual leukocyte populations [4], and the MHC class I-like molecule CD1d, recognized by natural killer T cells (‘NKT’) cells [5]. The establishment of the mammalian placenta a highly dynamic and invasive process that has, at its core, a fetusderived cell called the trophoblast [6]. This trophectodermderived cell lineage gives rise to both the syncytiotrophoblast, the critical hormone-producing outermost layer of the blastocyst, and the invasive extravillous trophoblasts, so named because of their ability to migrate from anchoring chorionic villi. Extravillous trophoblasts migrate throughout the decidua, reshaping and remodeling maternal tissue as they secrete a variety of matrix metalloproteinases, until they reach their ultimate destination which is the maternal spiral arterioles (Fig. 1). There, the extravillous trophoblasts invade and replace the endothelium of the maternal blood vessels, transforming them into relatively low-resistance conduits that promote 1521-6616/$ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2011.09.004
proper perfusion of the placenta. It is generally agreed upon that impaired trophoblast invasion and remodeling of the maternal tissues underlies disorders of pregnancy such as preeclampsia and intra-uterine growth retardation [6]. Throughout their migration through the decidua, trophoblasts are in intimate contact with maternal decidual leukocytes, which comprise anywhere from 10 to 25% of all cells in the decidua [7]. In general, innate-like immune cells are enriched in epithelial tissues such as lung, skin, intestine, and liver, and in this, the decidua is no different. Although CD4 +, CD8 +, and regulatory T cells are present, the maternal decidual leukocyte population early in gestation is characterized largely by cells of the innate arm. Macrophages are abundant, as are CD16 −CD56 bright decidual NK cells, which can comprise up to 70% of the decidual lymphocyte population [7], and NKT cells [5]. The report by Fan et al. [1] now adds to previous studies showing that a sizeable fraction of the decidual CD3 + T cell population is dominated by the innate-like gamma delta (γδ) T subset. In humans and rodents, classical αβ T cells outnumber γδ T cells in most lymphoid organs by more than 10:1 and γδ T cells represent ~1–10% of total PBMC T cells [8]. In ruminants, however, the reverse is true [8]. Unlike classical αβ T cells, the limited TCR repertoire of γδ T cells recognizes a range of non-peptidic antigens that are not MHC-restricted. γδ T cell antigens began to be identified in the 1990s [8,9]. Vδ1+ T cells can recognize the stress-inducible MHC-related molecules MICA/B and other ligands [8,9]. A major γδ T cell subset in peripheral blood mononuclear cells (PBMC) of healthy humans are Vγ9Vδ2+ T cells. The Vγ9Vδ2+ T cell TCR recognizes natural phosphonates [isopentenyl pyrophosphate (IPP)] and synthetics (e.g. BrHPP/Bromohydrin pyrophosphate and HMBPP/Hydroxy–methyl–butenyl–pyrophosphate) phosphoantigens [8,9]. Such phosphoantigens can be overexpressed by tumor cells, possibly due to metabolic stress, which can activate Vγ9Vδ2+ T cell cytotoxicity [8,9]. Hence Vγ9Vδ2+ T cells also have anti-tumor potential. Zoledronate induces the formation of metabolites like isopentyl phosphates, which can be recognized by γδ T cells, specifically
Editorial
237
Figure 1 Schematic of the human maternal-fetal interface. On the right is a close-up view of a single chorionic villous. Fetus-derived trophoblasts give rise to both the syncytiotrophoblast, the hormone-producing outermost layer of the chorionic villi, and the invasive extravillous trophoblasts (EVTBs), so named because of their ability to migrate from anchoring chorionic villi. EVTBs migrate through the decidua, eventually invading the maternal spiral arterioles, transforming them into relatively low-resistance blood vessels that promote proper perfusion of the placenta.
the Vγ9Vδ2+ subset [10,11]. This is a significant aspect, given that zoledronate is an approved drug for the prevention of bone resorption due to local metastases from a variety of cancers. There has been a recent flurry of papers describing the effects of zoledronate on γδ T cells, including clinical trials of zoledronate used directly in vivo with IL-2 or for ex vivo expansion of γδ T cells for cell therapy [11–13]. In contrast to blood, decidual γδ T cells can have more of other subsets. Both Vδ1+ and Vγ9Vδ2+ T cells with regulatory phenotype are found in decidua [14–18]. A cloning study showed that there maybe microanatomical heterogeneity, in that decidua parietalis has b50% Vγ9Vδ2+ T cells and more than 50% are Vδ1+ T cells (b 15% of PBMC γδ T cells). Decidual basalis γδ T cells were ~95% Vγ9Vδ2+ T cells [19], a higher proportion than in blood. In a histochemical study, γδ T cells were scattered in the endometrial/decidual stroma [20]. Of course, these fractions may vary during pregnancy. What then is the potential function of decidual γδ T cells? Fan et al. [1] examine γδ T cells in the human decidua, finding that they are predominantly CD4–CD8- ‘double negative’ (DN) T cells with overall regulatory (Treg) phenotype. Extending earlier reports [14–18], they find that these cells are highly biased toward IL-10 and TGF-β1 production. Also present are IFN-γ and TNF-α-producing γδ T cells, but these comprise only a minor population. Although not investigated by Fan et al., it may be of interest to determine whether the γδ T cell population is comprised of multiple subsets (i.e., an IFN-γ/TNF-producing subset and an IL-10/ TGF-β1-producing subset) or whether a fraction of the decidual γδ T cells can produce simultaneously Th1-like and Treg-type cytokines, similar to NKT cells. Importantly, Fan
et al., extend these findings by demonstrating that coculture of decidual γδ T cells with trophoblasts promotes trophoblast proliferation and attenuates trophoblast apoptosis [1]. They go on to demonstrate that these functions are mediated in large part by IL-10. Consistent with this finding is their demonstration that IL-10 produced by γδ T cells promotes trophoblast invasion through extracellular matrix in vitro [1]. The report by Fan et al., provides further support for the notion that the recognition of fetal cells by the maternal immune system need not have only negative consequences. This is consistent with reports that decidual NK cells release IL-8 and IP-10 chemokines that act on trophoblast cells, promoting their invasion into the endometrium [21,22]. Decidual NK cells also produce proangiogenic VEGF and PLGF, which can induce endothelial activation and aid in the establishment of placental vasculature [21]. In addition, ligands for the decidual NK cell activating receptors NKp44 and NKp30 can be expressed by maternal stromal cells (both ligands) and by trophoblast cells (NKp44) [21]. Indeed, given that decidual NK cells can also produce IL-10 [23], one wonders to what extent do the functions of decidual NK and γδ T cells overlap. Or, is it the case that the overall inflammatory environment in which the decidual NK cells are immersed is balanced by the more regulatory ‘flavor’ of decidual γδ T cells? There is another possibility too, given recent results that IL-10 appears to protect activated NK cells from apoptosis [24], which may allow NK cells to perform their role in decidua too. Clearly, despite potential modest human–animal differences, direct in vivo model experiments are warranted for definitive testing of the hypothesis proposed by Fan [1], that
238 IL-10 produced by γδ T cells contributes to trophoblast invasion and thereby successful pregnancy. However, the regulatory phenotype of human decidual γδ T cells clearly supports their potential to contribute toward maintenance of a noninflammatory micro-environment. Further results have linked failure of this regulatory activity of human decidual γδ T cells to pathological outcomes in pregnancy [18,25,26]. In general, results in mouse [27–32] and large animal models [33,34] also support the emerging protective role of decidual γδ T cells.
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Mark A. Exley Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA Corresponding author. Fax: + 1 617 667 0610. E-mail address: [email protected]. Jonathan E. Boyson Dept. of Surgery, University of Vermont College of Medicine, Burlington, VT, USA