Adaptation and Modulation of Memory and Regulatory T Cells in Pregnancy
Kieffer, Tom Eduard Christiaan
DOI:
10.33612/diss.97355536
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2019
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Kieffer, T. E. C. (2019). Adaptation and Modulation of Memory and Regulatory T Cells in Pregnancy. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.97355536
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
General Introduction
GENERAL INTRODUCTION
Pregnancy is an exceptional immunological phenomenon. Normally, the immune system generates an immune response upon activation by non-self antigens to clear the non-self antigen presenting body1. However, during pregnancy specific immune
adaptations prevent this immune response towards fetal-paternal antigens2,3, while
immunity towards pathogens remains intact4. Thus, the maternal immune system adapts
to prevent rejection of the semi-allogeneic cells of the fetus and with that fetal-maternal immune tolerance is generated.
Insufficient adaptations of the maternal immune system may contribute to dysfunc-tional fetal-maternal immune tolerance, which is implicated in the pathophysiology of pregnancy disorders such as infertility, pregnancy loss, fetal growth restriction, and preeclampsia5–7, which affect both mother and child. The exact mechanisms
responsible for fetal-maternal immune tolerance are incompletely understood. Studies into the immunology of pregnancy aim to elucidate the function and dysfunction of these mechanisms. Ultimately, these studies will contribute to development of medical interventions, possibly through modulation of the immune response, to prevent or treat pregnancy disorders.
The concept of fetal-maternal immune tolerance
After previous studies implying immunologic tolerance by Ray Owen8,9, in 1953, Sir
Peter Medawar was the first to conclusively show experimentally induced immunologic tolerance in mice10. In the same year, he acknowledged the unique phenomenon
of the allogeneic fetus being carried by the mother without rejection and posed: “How does the pregnant mother contrive to nourish within itself, for many weeks or months, a foetus that is an antigenically foreign body?”11. Medawar hypothesized
that fetal-maternal tolerance is explained by three mechanisms. Firstly, by physical separation between the mother and fetus, secondly by antigenic immaturity of the fetus, and thirdly, by immunological inertness of the mother. However, it has now conclusively been shown that the three hypotheses of Medawar are invalid12–16.
Firstly, absolute physical separation between the mother and fetus does not exist. It is known that fetal cells are in direct contact with the maternal blood and even per-sist in the maternal circulation many years after pregnancy, i.e. microchimerism12,13.
antige-statement, regarding maternal inertness, has been shown to be incorrect as the mater-nal immune system is still able to generate an immune response towards pathogens during pregnancy4, and fetal-antigen specific lymphocytes have been shown which
are able to generate fetal-antigen specific tolerance15,16. Thus, the maternal immune
system actively responds to fetal antigens, does not reject fetal cells, and actively establishes fetal-maternal immune tolerance.
After Medawar, numerous studies attempted to explain the mechanisms of maternal tolerance towards the fetus. Although our knowledge on immunology of pregnancy has improved, the exact mechanisms are still incompletely understood.
Immunology of pregnancy
As described above, fetal trophoblasts are in direct contact with maternal immune cells in decidual tissue of which two subtypes are distinguished17,18. The uterine lining
located around the fetal membranes is called the decidua parietalis and interacts with chorionic trophoblasts17. The decidua basalis is part of the placenta and is
invaded by extravillous trophoblasts and due to its anatomic location has a different blood supply18. Interaction of the maternal immune cells with fetal trophoblasts results
in recruitment of specific immune cells from the blood19. Due to different amounts
of antigen exposure, cell recruitment, and blood supply the immune cell repertoire greatly varies between different tissues during pregnancy. Fetal syncytiotrophoblasts cells are in contact with the maternal blood circulation and therefore with circulating maternal immune cells20. This indicates that specific adaptations are also needed in
circulating maternal immune cells.
Adaptations of both the innate and adaptive immune system are required for maintaining fetal-maternal immune tolerance and pregnancy success21. The innate
immune system is the first line of immune defence of the human body and consists of epithelia, phagocytic cells (monocytes, neutrophils, and macrophages), natural killer (NK) cells, blood proteins (inflammatory mediators and parts of the complement system) and cytokines1. Adaptations of innate immune cells in pregnancy include
activation, increased numbers and altered function of monocytes3,22, granulocytes23,
and NK cells24. Together with many more adaptations, the innate immune system
greatly attributes to fetal-maternal tolerance in the peripheral circulation and at the fetal-maternal interface, where they are especially important in the processes of spiral artery remodeling and placental development25. This thesis focuses on the adaptive
immune system which is divided into two subtypes i.e. humoral and cellular immunity1.
The humoral immune response protects against extracellular micro-organisms and is managed by B-lymphocytes (B cells) mostly1. The main mediators of cellular immunity
are T lymphocytes (T cells)1,26. T cells are the most studied immune cells in pregnancy
and the main interest of this thesis26.
T cells develop from haematopoietic stem cells in the bone marrow and mature in the thymus in the juvenile, thereafter the T cell population is maintained by division of mature T cells outside the primary lymphoid organs1,27. They are identified by their
T cell receptor (TCR) which recognizes antigens presented in the context of major histocompatibility complexes (MHC) by other cells28. Different types of T cells are
distinguished according to the class of MHC the cell responds to. CD8+ T cells, or
cytotoxic T lymphocytes, recognize antigens on MHC class I molecules expressed on all nucleated cells and platelets, whereas CD4+ T cells, or helper T lymphocytes,
respond to antigens presented on MHC class II molecules expressed on antigen presenting cells such as macrophages and dendritic cells28. CD4+ cells can produce
cytokines and thereby affect the response of several other immune cells, coordinating the immune response1. Most of the CD8+ cells are considered cytotoxic and act by
killing cells through secretion of pro-inflammatory cytokines or through apoptosis induction by cell-cell interaction with the target cell1.
Figure 1. Schematic overview of the anatomy of the placenta, decidual tissue, and membranes. Source: Fleischer’s Sonography in Obstetrics and Gynecology: Textbook and Teaching Cases, 8th edition; Chap-ter 7: Placenta, Cord, and Membranes; Authors: J.M. Mastrobattista, E.C. Toy. Copyright © 2018 by McGraw-Hill Education.
Based on their effector function, the CD4+ cell compartment is divided into several
subsets. In the CD8+ cell compartment on the other hand, subsets based on effector
function are rarely used29. The CD4+ cell compartment is subdivided into several
subsets of which the T helper 1 (Th1), Th2, Th17, and T regulatory (Treg) cell sub-sets, are the mostly studied1. Expression of transcription factor TBET, induces
diffe-rentiation of T cells towards Th1 cells which are known for their pro-inflammatory immune response towards bacteria and protozoa, and are characterized by IFNγ secretion30,31. Th2 cells, differentiated from effector T cells with over expression of
transcription factor GATA3, manage the immune response towards parasites and produce interleukin-4 (IL4), IL5, and several other cytokines30,31. They can also regulate
anti-inflammatory processes by secretion of IL10 which can suppress the Th1 response and dendritic cell function32. Th17 cells are recognized by RORγT expression and
IL17 production and therewith generate a pro-inflammatory response and inhibit Treg cell differentiation33–35. Treg cells have immune regulatory and anti-inflammatory
abilities and are of particular interest in fetal-maternal tolerance36,37. Treg cells are
studied in more detail in this thesis and are more elaborately introduced below38.
T cells are also divided into naïve cells, effector cells, and memory cells39. This
subdivision is made in both CD4+ and CD8+ T cell subsets and is based on antigen
experience of the cells39. The naïve T cell population represents the cells that have
never been activated through antigen exposure. Effector cells have been activated by antigens and are executing effector functions, whereas memory T cells were pre-viously activated by antigen and remain waiting for a secondary encounter with the same antigen to elicit a more enhanced response39. Increasing evidence implies a
role for memory T cells in fetal-maternal tolerance and these cells are therefore further studied in this thesis40. Immune cell subsets are also characterized by specific
migra-tory patterns41. Whereas some immune cells only circulate in peripheral blood and
lymph nodes, other immune cells stay resident in one tissue their entire lifespan42,43.
T regulatory cells
Treg cells in the CD4+ cell lineage are identified by transcription factor forkhead
box p3 (FOXP3), and are also known to express high levels of CD25 (IL2Rα) and low levels of CD127 (IL7Rα)44. Most studies focus on CD4+ Treg cells, but Treg cells with
a CD8+ background are also described45,46. CD8+ Treg cells are not identified by
Foxp3 expression but mainly by their immune regulatory cytokine secretion profile45,47.
They are less prevalent, more difficult to identify, and are not studied much in repro-duction. In this thesis, CD8+ Treg cells are not further studied.
CD4+ Treg cells are capable of suppressing CD4+, CD8+ and B cell proliferation and
cytokine secretion through several pathways such as secretion of IL10 and transforming growth factor beta (TGFβ) and expression of CD3948–52. Together with their inhibiting
effects on antigen presenting cells, such as dendritic cells and macrophages, they have controlling abilities on both the adaptive and the innate immune response53,54.
Their immune regulatory function is implicated in physiological and pathological contexts such as gastro-intestinal homeostasis55, auto-immune diseases56, respiratory
disorders57, and oncological pathology58.
Aluvihare et al. was the first to describe the essential role for Treg cells in fetal-ma-ternal tolerance by showing rejection of semi-allogeneic fetuses in Treg cell depleted mice36. Later, it was reported that adaptations of the Treg cell population occur even
before embryo implantation and are essential for reproductive success59. Robertson
et al. showed that seminal fluid is one of the mediators of the accumulation of Treg cells in the mouse uterus before implantation60,61. Recently, Treg cell abundance in the
mouse uterus in early pregnancy was found to be involved in uterine artery function and decreasing oxidative stress62.
The importance of Treg cells in successful reproduction was also found in humans37,63.
In healthy human pregnancy, Treg cell numbers increase, with a peak in the second trimester, and a clear decline in the weeks before spontaneous labor64–66. Insufficient
adaptations of the Treg cell population in human pregnancy are implicated in the pathophysiology of many complications of reproduction as infertility38,67, pregnancy
loss68, and preeclampsia38,69,70. In preeclampsia, decreased numbers and Treg cells
with dysfunctional immune regulatory function are associated with a more pro-inflam-matory state towards the fetal-placental unit70–72.
Upon antigen exposure, the Treg cell population expands and after the immune response most Treg cells perish through apoptosis46. However, a population of Treg
cells differentiates into Treg memory cells and persists in either secondary lymphoid organs, the blood circulation or remain resident in the tissue73–75. Treg memory cells
are further discussed in chapter 2 of this thesis.
Memory T cells
Immunologic memory is defined as the ability of the immune system to remember anti-gens and mount a response of greater magnitude and faster kinetics on a secondary
encounter with the same antigen76. Immunologic memory is formed by T cells, B cells
and recently natural killer cells were also found to have memory capabilities77–79.
Memory T cells are formed during an immune response. Whereas most effector T cells die, some effector T cells differentiate into memory T cells and remain present to rapidly re-accumulate upon a secondary encounter with the memorized antigen80.
The secondary response elicits a much quicker expansion of the T cell population, higher levels of cytokine secretion, and faster elimination of the allogeneic body80.
In pregnancy, long time surviving memory T cells are formed with specificity for fetal-paternal antigens81–83. However, instead of quick elimination of fetal cells upon
a second encounter with the fetal-paternal antigens, in pregnancy, immune tolerance towards the fetal cells is required for pregnancy success. Increasing evidence shows that altered numbers and function of memory T cells in pregnancy are important for pregnancy success and a beneficial role is suggested16,81,84,85. Moreover, insufficient
adaptations of memory T cell populations are implicated in the pathophysiology of pregnancy complications such as preeclampsia70,81,84,86. In chapter 2 memory T cells
and their subsets are introduced and their involvement in pregnancy and in pregnancy complications are discussed.
Preeclampsia
Preeclampsia is characterized by de-novo hypertension, together with either pro-teinuria, maternal organ dysfunction (including liver involvement, neurological com-plications, or haematological complications), or fetal growth restriction87, though
symptomless pre-clinical stages precede88. This hypertensive disorder complicates
2-8% of pregnancies89. Together with gestational- and chronic hypertension, it affects
5-10% of all pregnancies and causes 3-5% of maternal deaths in high-income coun-tries and up to 26% in Latin America and the Caribbean90–92. Its associated fetal
growth restriction and (iatrogenic) preterm birth are associated with an increase in fetal morbidity and mortality93. Besides an increased risk of preeclampsia in a
subse-quent pregnancy, long term effects of preeclampsia for women with a preeclamptic pregnancy in their obstetric history include hypertension, cardiovascular diseases, diabetes mellitus, and renal dysfunction93–95. Long term effects on offspring are not
studied as much as long term maternal effects, but reduced cognitive performance96,97,
and increased risks of high blood pressure and stroke in adolescence have been shown93,98.
After decades of research, the multifactorial pathophysiology of preeclampsia is still incompletely understood. Evidence of several pathways is reported, and most likely each case has a unique combination of factors in its aetiology with involvement of multiple mechanisms that work intertwined. As an attempt to categorize different types of preeclampsia by its aetiology, early-onset and late-onset preeclampsia are distinguished99. Early-onset, defined as diagnosis before 34 weeks of gestation, is
considered to be mainly caused by disturbance in placentation and is associated with fetal growth restriction100,101. Late-onset preeclampsia, diagnosed after 34 weeks
of gestation, is supposedly associated with ageing of the placenta and reduced intervillous perfusion and does not cause fetal growth restriction in most cases100,101.
It is proposed that the preclinical stage of early-onset preeclampsia starts early in pregnancy with abnormal invasion of trophoblast cells in the myometrium102. Poor
placentation, as demonstrated by insufficient spiral artery remodelling, may lead to insufficient uteroplacental circulation103. The clinical stages of preeclampsia are
most likely caused by oxidative stress due to factors coming from the dysfunctional placenta resulting in a systemic inflammatory response of the mother104. It is proposed
that one of the underlying dysfunctions in preeclampsia would be insufficiency of the maternal immunologic adaptations to tolerate the fetal cells105. Presumably, the
immune cells do not adequately regulate the processes in early pregnancy such as myometrial trophoblast invasion, essential for normal implantation and remodelling of the spiral arteries to form a low resistance flow network supplying the intervillous space105. Instead, they induce an inflammatory response towards the fetal placental
unit, possibly resulting in pregnancy induced hypertension in mild cases, to pree-clampsia and pregnancy loss when more severe100,104.
A great variety of immune cells from both the innate and adaptive immune system are implicated in the pathophysiology of preeclampsia. As indicated above, the immune response during normal pregnancy has to adapt in order to tolerate the semi-allogeneic fetus. However, during preeclampsia this adaptation may fail21,105,
resulting in aberrant immune responses during preeclampsia. For instance, inadequate maternal NK cell interaction with fetal antigens in early pregnancy has been found to induce insufficient immune regulation of placental development106. Reduced Treg
cell numbers, as found in preeclampsia69,71, may cause the imbalance in Th1, Th2,
and Th17 cells which results in secretion of pro-inflammatory cytokines and aberrant activation of innate immune cells3, resulting in the systemic inflammatory response
Epidemiologic evidence implies a role for immunologic memory in the pathophysio-logy of preeclampsia. Where at first it was believed that preeclampsia was a disease of first-time mothers, in 1994 it was found that the lower risk of preeclampsia in a subsequent pregnancy was lost with a change of partner and was thus associated with primipaternity107,108. Thereafter, it was shown that a longer period of regular
exposure to seminal fluid to the vaginal or oral mucosa before conception contributes to a lower risk of early-onset preeclampsia109–111. These findings suggest that
immuno-logic memory, and possibly memory T cells, have beneficial effects during pregnancy.
Aim and outline of this thesis
This thesis aims to analyse the adaptations of memory- and Treg cells in healthy- and complicated pregnancies, and to explore the effects of modulation of the immune response on pregnancy and pregnancy outcome. We aim to increase knowledge on memory- and Treg cells in healthy pregnancies and preeclampsia.
In this thesis, memory T cells and / or regulatory T cells are investigated in preg-nancy in three different settings; physiology, pathology, and after immune modulatory treatment such as prednisolone.
In chapter 2 a detailed introduction on the current state of the art knowledge on memory T cells in pregnancy is provided.
Part 1 starts with chapter 3, which gives insight into the persistent effects of normal human pregnancy on the memory T cell (sub)populations in peripheral blood of healthy women. In chapter 4 focus will be on memory T cell populations at the fetal-mater-nal interface in healthy pregnancies, and alterations of memory T cells in decidual tissue of first pregnancies compared to pregnancies of women who delivered before. In chapter 5, alterations of the maternal immune response in early pregnancy asso-ciated with fetal sex are described. This chapter emphasizes the importance of the consideration of fetal sex in further investigations into the immunology of pregnancy and the delicacy of the immune balance in uncomplicated pregnancies.
In part 2, memory T cells are studied in a pathological condition; preeclampsia. In chapter 6, memory T cell populations are studied in peripheral blood of preeclamp-tic and healthy pregnant women, and women postpartum after a preeclamppreeclamp-tic or healthy pregnancy. In this study, we aimed to show the short- and long term effects of preeclampsia on memory T cell populations in peripheral blood. Chapter 7, provides
insight into proportions of memory T cell subsets in preeclampsia, by studying decidual tissue from preeclamptic and uncomplicated pregnancies.
Part 3 of this thesis focuses on modulation of the immune response in pregnancy as
a treatment for pregnancy complications. First, in chapter 8, different possibilities of immunomodulatory treatments to treat recurrent miscarriage are reviewed. In
chap-ter 9, one of the immunomodulatory treatments is investigated further in a mouse
model. The effects of prednisolone treatment in early pregnancy on maternal Treg cells are reported. In addition, the long-term effects on offspring are investigated to gain knowledge on the importance of sufficient maternal immune adaptations in pregnancy for the offspring.
In chapter 10, the findings reported in this thesis are discussed in relation to one another and proposals for future research into memory- and regulatory T cells in pregnancy are proposed.
REFERENCES
1. Abbas, A. K., Lichtman, A. H. & Pillai, S. Cellular and Molecular Immunology. 9, (Elsevier Saunders, 2017).
2. Guerin, L. R., Prins, J. R. & Robertson, S. A. Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment? Hum. Reprod. Update 15, 517–535 (2009).
3. Faas, M. M., Spaans, F. & De Vos, P. Monocytes and Macrophages in Pregnancy and Pre-Eclampsia. Front. Immunol. 5, 298 (2014).
4. Lashley, L. E. E. L. O. et al. Changes in cytokine production and composition of
peripheral blood leukocytes during pregnancy are not associated with a difference in the proliferative immune response to the fetus. Hum. Immunol. 72, 805–811 (2011).
5. Sibai, B., Dekker, G. & Kupferminc, M. Pre-eclampsia. Lancet 365, 785–99 (2005). 6. Cudihy, D. & Lee, R. The pathophysiology of pre-eclampsia: current clinical concepts.
J. Obstet. Gynaecol. 29, 576–582 (2009).
7. Zenclussen, A. C. Adaptive immune responses during pregnancy. Am. J. Reprod.
Immunol. 69, 291–303 (2013).
8. Owen, R. D. Immunogenetic consequences of vascular anastomoses between bovine twins. Science (80-. ). 102, 400–401 (1945).
9. F. M., B. & F., F. The Production of Antibodies. Macmillan, London 2nd ed., 103 (1949). 10. Billingham, R. E., Brent, L. & Medawar, P. B. Actively acquired tolerance of foreign cells.
Nature 172, 603–6 (1953).
11. Medawar, P. B. in Symp. Soc. (1953).
12. Nelson, J. L. Your cells are my cells. Sci. Am. 298, 64–71 (2008).
13. Bianchi, D. W., Zickwolf, G. K., Weil, G. J., Sylvester, S. & DeMaria, M. A. Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc. Natl.
Acad. Sci. U. S. A. 93, 705–8 (1996).
14. Arck, P. C. & Hecher, K. Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat. Med. 99, 548–556 (2013).
15. Tafuri, A., Alferink, J., Moller, P., Hammerling, G. J. & Arnold, B. T cell awareness of paternal alloantigens during pregnancy. Science 270, 630–633 (1995).
16. Kahn, D. A. & Baltimore, D. Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance. Proc. Natl. Acad. Sci.
U. S. A. 107, 9299–304 (2010).
17. Baergen, R. N. in Manual of Benirschke and Kaufmann’s 80–95 (Springer-Verlag, 2005). 18. Baergen, R. N. in Manual of Benirschke and Kaufmann’s 107–134
(Springer-Verlag, 2005).
19. Tilburgs, T. et al. Evidence for a selective migration of fetus-specific CD4+CD25bright regulatory T cells from the peripheral blood to the decidua in human pregnancy.
J. Immunol. 180, 5737–45 (2008).
20. Wang, Y. & Zao, S. Vascular Biology of the Placenta. (Morgan & Claypool Life Sciences, 2010).
21. Hsu, P., Nanan, R. K. & Hsu Ralph Kay Heinrich, P. N. Innate and Adaptive Immune Interactions at the Fetal-Maternal Interface in Healthy Human Pregnancy and Pre-Eclampsia. Front. Immunol. 5, 125 (2014).
22. Luppi, P. et al. Monocytes are progressively activated in the circulation of pregnant women. J. Leukoc. Biol. 72, 874–84 (2002).
23. Matthiesen, L., Berg, G., Ernerudh, J. & Håkansson, L. Lymphocyte Subsets and Mitogen Stimulation of Blood Lymphocytes in Normal Pregnancy. Am. J. Reprod. Immunol. 35, 70–79 (1996).
24. Veenstra van Nieuwenhoven, A. L. et al. Cytokine production in natural killer cells and lymphocytes in pregnant women compared with women in the follicular phase of the ovarian cycle. Fertil. Steril. 77, 1032–1037 (2002).
25. Smith, S. D., Dunk, C. E., Aplin, J. D., Harris, L. K. & Jones, R. L. Evidence for Immune Cell Involvement in Decidual Spiral Arteriole Remodeling in Early Human Pregnancy.
Am. J. Pathol. 174, 1959–1971 (2009).
26. Scherjon, S., Lashley, L., Van Der Hoorn, M. L. & Claas, F. Fetus specific T cell modulation during fertilization, implantation and pregnancy. Placenta (2011). 27. Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in
Health and Disease. (Garland Science, 2001).
28. Rudolph, M. G., Stanfield, R. L. & Wilson, I. A. How TCRs bind MHCs, peptides, and coreceptors. Annu. Rev. Immunol. 24, 419–466 (2006).
29. Liang, Y., Pan, H.-F. & Ye, D.-Q. Tc17 Cells in Immunity and Systemic Autoimmunity. Int.
Rev. Immunol. 34, 318–331 (2015).
30. Zhu, J. & Paul, W. E. CD4 T cells: fates, functions, and faults. Blood 112, 1557–69 (2008).
31. Kanhere, A. et al. T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nat. Commun. 3, 1268 (2012). 32. Berger, A. Th1 and Th2 responses: what are they? 321, 424 (2000).
33. Hartigan-OʼConnor, D. J., Hirao, L. A., McCune, J. M. & Dandekar, S. Th17 cells and regulatory T cells in elite control over HIV and SIV. Curr. Opin. HIV AIDS 6, 221–227 (2011).
34. Zhou, L. et al. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453, 236–240 (2008).
35. Ivanov, I. I. et al. The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells. Cell 126, 1121–1133 (2006). 36. Aluvihare, V. R., Kallikourdis, M. & Betz, A. G. Regulatory T cells mediate maternal
tolerance to the fetus. Nat. Immunol. 5, 266–271 (2004).
37. Sasaki, Y. et al. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol. Hum. Reprod.
10, 347–353 (2004).
38. Guerin, L. R., Prins, J. R. & Robertson, S. A. Regulatory T-cells and immune tolerance in pregnancy: A new target for infertility treatment? Hum. Reprod. Update 15, 517–535 (2009).
39. Sallusto, F., Lenig, D., Förster, R., Lipp, M. & Lanzavecchia, A. A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature
401, 708–712 (1999).
40. Kieffer, T. E. C., Laskewitz, A., Scherjon, S. A., Faas, M. M. & Prins, J. R. Memory T Cells in Pregnancy. Front. Immunol. 10, 625 (2019).
41. Krummel, M. F., Bartumeus, F. & Gérard, A. T cell migration, search strategies and mechanisms. Nat. Rev. Immunol. 16, 193–201 (2016).
42. Kumar, B. V. et al. Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites. Cell Rep.
20, 2921–2934 (2017).
43. Mueller, S. N., Gebhardt, T., Carbone, F. R. & Heath, W. R. Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 31, 137–161 (2013). 44. Hori, S., Nomura, T. & Sakaguchi, S. Control of Regulatory T Cell Development by the
Transcription Factor Foxp3. Science (80-. ). 299, 1057–1061 (2003).
45. Wang, S. et al. PD-1 and Tim-3 pathways are associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy. Cell Death Dis.
6, e1738 (2015).
46. Rosenblum, M. D., Way, S. S. & Abbas, A. K. Regulatory T cell memory. Nat. Rev.
47. Machicote, A., Belén, S., Baz, P., Billordo, L. A. & Fainboim, L. Human CD8+HLA-DR+ Regulatory T Cells, Similarly to Classical CD4+Foxp3+ Cells, Suppress Immune Responses via PD-1/PD-L1 Axis. Front. Immunol. 9, 2788 (2018).
48. Sakaguchi, S., Wing, K., Onishi, Y., Prieto-Martin, P. & Yamaguchi, T. Regulatory T cells: how do they suppress immune responses? Int. Immunol. 21, 1105–1111 (2009).
49. Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–65 (2007). 50. Shevach, E. M. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity
30, 636–45 (2009).
51. Piccirillo, C. A. & Shevach, E. M. Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J. Immunol. 167, 1137–40 (2001).
52. Lim, H. W., Hillsamer, P., Banham, A. H. & Kim, C. H. Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J. Immunol. 175, 4180–3 (2005). 53. Misra, N., Bayry, J., Lacroix-Desmazes, S., Kazatchkine, M. D. & Kaveri, S. V. Cutting
edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J. Immunol. 172, 4676–80 (2004).
54. Taams, L. S. et al. Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum. Immunol. 66, 222–230 (2005).
55. Barnes, M. J. & Powrie, F. Regulatory T Cells Reinforce Intestinal Homeostasis. Immunity
31, 401–411 (2009).
56. Dominguez-Villar, M. & Hafler, D. A. Regulatory T cells in autoimmune disease. Nat.
Immunol. 19, 665–673 (2018).
57. Tosiek, M. J. et al. CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation. J. Immunol. 186, 6106–6118 (2011).
58. Shitara, K. & Nishikawa, H. Regulatory T cells: a potential target in cancer immunotherapy. Ann. N. Y. Acad. Sci. 1417, 104–115 (2018).
59. Zenclussen, A. C. et al. Abnormal T-Cell Reactivity against Paternal Antigens in Spontaneous Abortion. Am. J. Pathol. 166, 811–822 (2005).
60. Robertson, S. A. et al. Seminal fluid drives expansion of the CD4+CD25+ T regulatory cell pool and induces tolerance to paternal alloantigens in mice. Biol. Reprod.
80, 1036–45 (2009).
61. Guerin, L. R. et al. Seminal Fluid Regulates Accumulation of FOXP3+ Regulatory T Cells in the Preimplantation Mouse Uterus Through Expanding the FOXP3+ Cell Pool and CCL19-Mediated Recruitment. Biol. Reprod. 85, 397–408 (2011).
62. Care, A. S. et al. Reduction in Regulatory T Cells in Early Pregnancy Causes Uterine Artery Dysfunction in Mice. Hypertens. (Dallas, Tex. 1979) 72, 177–187 (2018). 63. Mor, G., Aldo, P. & Alvero, A. B. The unique immunological and microbial aspects of
pregnancy. Nat. Rev. Immunol. 17, 469–482 (2017).
64. Heikkinen, J., Mottonen, M., Alanen, A. & Lassila, O. Phenotypic characterization of regulatory T cells in the human decidua. Clin. Exp. Immunol. 136, 373–378 (2004). 65. Zhao, J., Zeng, Y. & Liu, Y. Fetal alloantigen is responsible for the expansion of
the CD4+CD25+ regulatory T cell pool during pregnancy. J. Reprod. Immunol.
75, 71–81 (2007).
66. Somerset, D. A., Zheng, Y., Kilby, M. D., Sansom, D. M. & Drayson, M. T. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology 112, 38–43 (2004).
67. Jasper, M. J., Tremellen, K. P. & Robertson, S. A. Primary unexplained infertility is associated with reduced expression of the T-regulatory cell transcription factor Foxp3 in endometrial tissue. Mol. Hum. Reprod. 12, 301–308 (2006).
68. Winger, E. E. & Reed, J. L. Low Circulating CD4+ CD25+ Foxp3+ T Regulatory Cell Levels Predict Miscarriage Risk in Newly Pregnant Women with a History of Failure. Am.
J. Reprod. Immunol. 66, 320–328 (2011).
69. Prins, J. R. et al. Preeclampsia is associated with lower percentages of regulatory T cells in maternal blood. Hypertens. Pregnancy 28, 300–311 (2009).
70. Nguyen, T. A., Kahn, D. A. & Loewendorf, A. I. Maternal—Fetal rejection reactions are unconstrained in preeclamptic women. PLoS One 12, e0188250 (2017).
71. Sasaki D Suzuki, D Sakai, M Ito, M Shima, T Shiozaki, A Rolinski,J Saito, S., Y. D. K. Proportion of peripheral blood and decidual CD4(+) CD25(bright) regulatory T cells in pre-eclampsia. Clin. Exp. Immunol. 149, 139–145 (2007).
72. Saito, S. & Sakai, M. Th1/Th2 balance in preeclampsia. J. Reprod. Immunol.
59, 161–173 (2003).
73. Rosenblum, M. D., Way, S. S. & Abbas, A. K. Regulatory T cell memory. Nat. Rev.
Immunol. 16, 90–101 (2016).
74. Rosenblum, M. D. et al. Response to self antigen imprints regulatory memory in tissues.
Nature 480, 538–42 (2011).
75. Loblay, R. H., Pritchard-Briscoe, H. & Basten, A. Suppressor T-cell memory. Nature 272, 620–622 (1978).
76. Zanetti, M. Immunological Memory. eLS (John Wiley & Sons, Ltd, 2013).
77. Wakim, L. M. & Bevan, M. J. From the thymus to longevity in the periphery. Curr. Opin.
Immunol. 22, 274–278 (2010).
78. Kurosaki, T., Kometani, K. & Ise, W. Memory B cells. Nat. Rev. Immunol.
15, 149–159 (2015).
79. Gamliel, M. et al. Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies. Cell 48, 951–962 (2018).
80. Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol.
22, 745–63 (2004).
81. Rowe, J. H., Ertelt, J. M., Xin, L. & Way, S. S. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature 490, 102–6 (2012).
82. Barton, B. M., Xu, R., Wherry, E. J. & Porrett, P. M. Pregnancy promotes tolerance to future offspring by programming selective dysfunction in long-lived maternal T cells.
J. Leukoc. Biol 101, 975–987 (2017).
83. Powell, R. M. et al. Decidual T Cells Exhibit a Highly Differentiated Phenotype and Demonstrate Potential Fetal Specificity and a Strong Transcriptional Response to IFN.
J. Immunol. 199, 3406–3417 (2017).
84. Tilburgs, T. et al. Human decidual tissue contains differentiated CD8+ effector-memory T cells with unique properties. J. Immunol. 185, 4470–7 (2010).
85. Klatzmann, D. et al. Protect Embryos at Implantation in Mice Self-Specific Memory Regulatory T Cells Self-Specific Memory Regulatory T Cells Protect Embryos at Implantation in Mice. J Immunol Mater. Suppl. 191, 2273–2281 (2013).
86. Kinder, J. M. et al. Cross-Generational Reproductive Fitness Enforced by Microchimeric Maternal Cells. Cell 162, 505–515 (2015).
87. Brown, M. A. et al. Hypertensive Disorders of Pregnancy: ISSHP Classification, Diagnosis, and Management Recommendations for International Practice. Hypertension
72, 24–43 (2018).
88. Redman, C. The six stages of pre-eclampsia. Pregnancy Hypertens. An Int. J. Women’s
Cardiovasc. Heal. 4, 246 (2014).
89. Steegers, E. A. P., von Dadelszen, P., Duvekot, J. J. & Pijnenborg, R. Pre-eclampsia.
Lancet 376, 631–44 (2010).
90. Hutcheon, J. A., Lisonkova, S. & Joseph, K. S. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract. Res. Clin. Obstet. Gynaecol.
25, 391–403 (2011).
91. Khan, K. S., Wojdyla, D., Say, L., Gülmezoglu, A. M. & Van Look, P.
F. A. WHO analysis of causes of maternal death: a systematic review. Lancet 367, 1066–1074 (2006).
92. Knight, M. et al. Saving Lives, Improving Mothers’ Care Maternal, Newborn and Infant
Clinical Outcome Review Programme. (2018).
93. Bokslag, A., van Weissenbruch, M., Mol, B. W. & de Groot, C. J. M. Preeclampsia; short and long-term consequences for mother and neonate. Early Hum. Dev. 102, 47–50 (2016).
94. Lykke, J. A. et al. Hypertensive Pregnancy Disorders and Subsequent Cardiovascular Morbidity and Type 2 Diabetes Mellitus in the Mother. Hypertension 53,
944–951 (2009).
95. Bellamy, L., Casas, J.-P., Hingorani, A. D. & Williams, D. J. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.
BMJ 335, 974 (2007).
96. Tuovinen, S. et al. Maternal hypertensive disorders in pregnancy and self-reported cognitive impairment of the offspring 70 years later: the Helsinki Birth Cohort Study.
Am. J. Obstet. Gynecol. 208, 200.e1-200.e9 (2013).
97. Ehrenstein, V., Rothman, K. J., Pedersen, L., Hatch, E. E. & Sorensen, H. T. Pregnancy-associated Hypertensive Disorders and Adult Cognitive Function Among Danish Conscripts. Am. J. Epidemiol. 170, 1025–1031 (2009).
98. Kajantie, E., Eriksson, J. G., Osmond, C., Thornburg, K. & Barker, D. J. P. Pre-eclampsia is associated with increased risk of stroke in the adult offspring. Stroke 40, 1176–1180 (2009).
99. Tranquilli, A. L., Brown, M. A., Zeeman, G. G., Dekker, G. & Sibai, B. M. The definition of severe and early-onset preeclampsia. Statements from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Pregnancy Hypertens. An Int. J. Women’s
Cardiovasc. Heal. 3, 44–47 (2013).
100. Staff, A. C. & Redman, C. W. G. in Preeclampsia, Comprehensive Gynecology and
Obstetrics (ed. Saito, S.) 157–172 (Springer Nature Singapore Pte Ltd. 2018, 2018).
101. Raymond, D. & Peterson, E. A Critical Review of Early-Onset and Late-Onset Preeclampsia. Obstet. Gynecol. Surv. 66, 497–506 (2011).
102. Huppertz, B. Placental Origins of Preeclampsia. Hypertension 51, 970–975 (2008). 103. Burton, G. J. & Jauniaux, E. Placental Oxidative Stress: From Miscarriage to
Preeclampsia. J. Soc. Gynecol. Investig. 11, 342–352 (2004).
104. Redman, C. W. G. & Sargent, I. L. Placental Stress and Pre-eclampsia: A Revised View.
Placenta 30, 38–42 (2009).
105. Redman, C. W. G. & Sargent, I. L. Immunology of Pre-Eclampsia. Am. J. Reprod.
Immunol. 63, 534–543 (2010).
106. Hiby, S. E. et al. Combinations of Maternal KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success. J. Exp. Med. 200, 957–965 (2004).
107. Robillard, P. Y. et al. Paternity patterns and risk of preeclampsia in the last pregnancy in multiparae. J. Reprod. Immunol. 24, 1–12 (1993).
108. Robillard, P. Y., Dekker, G. A. & Hulsey, T. C. Revisiting the epidemiological standard of preeclampsia: primigravidity or primipaternity? Eur. J. Obstet. Gynecol. Reprod. Biol.
84, 37–41 (1999).
109. Robillard, P. Y. et al. Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception. Lancet 344, 973–5 (1994).
110. Saftlas, A. F. et al. Cumulative exposure to paternal seminal fluid prior to conception and subsequent risk of preeclampsia. J. Reprod. Immunol. 101–102, 104–110 (2014). 111. Koelman, C. A. et al. Correlation between oral sex and a low incidence of
preeclampsia: a role for soluble HLA in seminal fluid? J. Reprod. Immunol. 46, 155–66 (2000).
