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Departments of Pediatrics, University of Western Ontario (M.J.v.d.H.), London, Canada N6C 2V5; Departments of Mathematics and Statistics (J.H.) and Biomedical Sciences (K.H., S.Ba., S.Bu.), University of Guelph, Guelph, Ontario, Canada N1G 2W1; Department of Molecular Immunology, State University of New York (S.S.E.), Buffalo, New York 14263; Department of Anatomy and Cell Biology, Queen’s University (B.A.C.), Kingston, Canada K7L 3N6; and Department of Obstetrics and Gynecology, University of Western Ontario (F.R.T.), London, Canada N6A 1C9
Address all correspondence and requests for reprints to: Dr. Marianne J. van den Heuvel, Department of Pediatrics, Child Health Research Institute, 800 Commissioner’s Road East, University of Western Ontario, London, Ontario, Canada N6C 2V5. E-mail: mvandenh{at}uwo.ca.
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Introduction |
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(IFN-) and IFN-inducible protein-10], secreted by endometria under the influence of progesterone (P4) (5). These cells differentiate to become a unique lymphocyte subset characterized by retained expression of 
4 integrin, leukocyte function-associated antigen-1, C-C chemokine receptor-1 (CCR1), CCR2, CCR5, CXC chemokine receptor-3 (CXCR3), CXCR4, and CX3CR1; increased expression of CD56; and de novo expression of estrogen receptor (ERß), and many express the proliferation marker Ki-67 (6, 7). NK cells form close associations with extravillous trophoblast and spiral arteries, where they are thought to regulate the depth of invasion through secretion of cytokines such as IL-4, IL-10, and IFN- (7, 8). In turn, cytokines secreted by macrophages modulate both NK cell activation and cytokine secretion.
In mice, through secretion of IFN- (9, 10), uterine NK (uNK) cells function to support terminal decidual cell differentiation and initiate changes to spiral artery structure that enable pregnancy-associated dilation and elongation (11, 12). Human dNK cells, like their murine uNK cell counterparts, express major angiogenic molecules, such as vascular endothelial and placental growth factors (13). If the roles of uNK cells in mice are analogous to those of dNK cells in humans, dNK cell support of decidualization can be linked to implantation success and, thus, fertility.
Murine uNK cell progenitors reside outside the uterus and are found in all lymphoid tissues, with enrichment in spleen during pregnancy (14). Mobilization of blood-borne lymphocytes to tissue depends on their sequential adhesive interactions with endothelial cells under wall shear stress induced by hemodynamic flow (15, 16). The L-selectin adhesion molecule initiates rolling and tethering of lymphocytes to specialized endothelial cells, whereas chemokines mediate integrin-dependent firm adhesion, before extravasation. Using an in vitro assay of this functional interaction (adhesion of lymphocytes to endothelium in frozen tissue sections under shear), we found that lymphocytes from human peripheral blood adhering to microvessels of gestation day (gd) 6–8 mouse decidua were enriched for CD56bright NK cells (14, 17). Although CD56bright NK cells comprise about 1% of blood lymphocytes, they were 75% of the adherent cells. Blood CD56bright NK cells intensely express L-selectin-homing receptor (18, 19) and display a specific array of chemokine receptors, CCR5, CCR7, CXCR3, CXCR4, and CX3CR1 (20). Expression of these molecules predisposes CD56bright cells to tissue-selective homing. Adhesion of CD56bright cells to uterine substrates from pregnant animals was shown to be L-selectin dependent (14, 17, 21). Furthermore, murine lymphocytes from pregnant or hormone-treated [17ß-estradiol (E2) or P4] animals showed increased L-selectin-binding activity. We postulate that hormonal fluctuations during the menstrual cycle induce novel regulatory events in lymphocyte-endothelial cell adhesion pathways that contribute to traffic of uNK progenitor cells from lymphoid tissue into blood, then subsequently into decidualizing endometrium (14).
The number of dNK cells in the human uterus increases dramatically 3–5 d after ovulation (1, 22). We recently demonstrated that the potential of a subset of peripheral blood NK cells for trafficking from the circulation was enhanced during a brief, periovulatory window that extends from 2–3 d before the LH surge to 1 d after the LH surge in unmedicated menstrual cycles of fertile, regularly cycling women (21). The CD56bright cell adhesion was restricted to vascular endothelium only in the decidua basalis of pregnant mouse uteri (21). A similar increase in adhesion of CD56bright cells could be induced by culture with E2, LH, or very low doses of P4 (21). Higher doses of P4 returned CD56bright cell adhesion to baseline levels. This suggests that a subset of blood CD56bright cells may initiate mobilization to the uterus in response to factors induced by rising plasma E2 levels and to the amount of LH found at the LH surge, resulting in increased trafficking ability, which is terminated by high post-ovulation levels of P4. Together with the finding that LH primes uterine receptivity in menopausal women attempting pregnancy using assisted reproductive technology (23), the data suggest that events induced at the LH surge may synchronize dNK progenitor cell migration to the uterus with uterine decidualization or that LH-induced activation of dNK progenitor cells enables migration to the uterus, where dNK cells themselves contribute to the optimal decidualization necessary for implantation.
In this study we address two questions. Firstly, whether adhesion of CD56bright cells changes in the interval from ovulation to the establishment of pregnancy. Secondly, whether exogenous hormone treatment alters the trafficking potential of blood NK cells. Two groups of patients undergoing assisted reproductive technology were assessed for the functional uterine homing potential of their circulating CD56bright cells before and after embryo transfer (ET). The patients were either having an unmanipulated cycle before transfer of banked frozen embryos or receiving exogenous hormones for controlled ovarian hyperstimulation, oocyte collection, in vitro fertilization, and transfer of freshly prepared embryos. A relationship was found between lymphocyte adhesive function and the establishment of pregnancy.
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Subjects and Methods |
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Women of reproductive age with primary female infertility of various etiologies, some of whom also had male partner infertility, were recruited to participate in this study by physicians in the Reproductive Endocrinology and Infertility Program at London Health Sciences Center. The study was approved by the health sciences research ethics board at University of Western Ontario, and all recruited patients were fully informed of the potential risks and signed consent forms before participation. The women were divided into two groups: those undergoing a natural monitored cycle for transfer of frozen embryos (FET) and those entered in an exogenous, controlled ovarian hyperstimulation (COH) protocol for in vitro fertilization. Exclusion criteria included lack of response to treatment or lack of embryos suitable for transfer.
Sequential analysis of serum hormone levels was performed for clinical monitoring of each treatment cycle. For study purposes, every other day, an additional 8.5 ml blood were drawn according to the schedule shown in Table 1
. Encoded samples were processed within 3 h of collection. Lymphocytes were separated on standard Ficoll-Hypaque gradients, adjusted to 5 x 107 cells/ml in 37 C RPMI 1640 medium (Sigma-Aldrich Corp., St. Louis, MO) with no additives and used immediately in adhesion and flow cytometric assays, as previously described (17, 21).
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Mice and tissue dissections
C57BL/6J (The Jackson Laboratory, Bar Harbor, ME), aged 8–16 wk, were used for timed matings, with the morning of the copulation plug designated gd0. All procedures were performed under approved animal utilization protocols (animal care committee, University of Guelph). Mice were killed on gd7, uteri were removed, and implantation sites were snap-frozen as described previously (17). Midsagittal sections were cryosectioned at 12 µm immediately before assay within 14 d of harvest, as previously described (21).
Antibodies
To detect CD56+ cells, aliquots of 5 x 106 lymphocytes were prelabeled with mouse anti-CD56-phycoerythrin (anti-CD56-PE; Immunotech, Beckman Coulter, Mississauga, Canada) at 1:100 for 20 min at room temperature. When cell numbers permitted, cell aliquots were incubated with 10 µg/ml function-blocking mAb specific for human L-selectin (CD62L, BD Pharmingen, Mississauga, Canada). The cell suspension was characterized by flow cytometric analysis using the following panel of mouse antihuman antibodies (Caltag Laboratories, Burlingame, CA); CD4 R-PE-8-fluorescein isothiocyanate (R-PE-8-FITC; 1:100), CD19-FITC (1:10), CD33–4D3-R-PE (1:10), CD34-FITC (1:10), and the above-described anti-CD56-PE. Isotype controls were mouse IgG2a FITC/R-PE (1:100), mouse IgG1-FITC (1:10), and mouse IgG1-R-PE (1:10).
Flow cytometry
Cells suspended in PBS were labeled for 30 min at room temperature, then washed twice with PBS containing 2% BSA and 0.01% sodium azide. Immediate analyses of cell data were performed on a FACScan using CellQuest software (BD Biosciences, San Jose, CA). Lymphocytes were defined by forward and side scatter properties.
Assay of cell adhesion under shear to frozen tissue sections
A modified Stamper Woodruff adhesion assay (14, 17) was performed, layering 5 x 106 CD56-PE labeled lymphocytes, in the presence or absence of function-blocking antibodies to L-selectin, in 100 µl RPMI 1640 medium with no additives onto cryosections of mouse uterine tissues. After 30 min of rotation at 112 rpm in a cold chamber, nonadherent cells were rinsed off, and the tissue was fixed. Double-blind analysis was performed by two independent researchers counting adherent CD56bright cells in 25 high power fields (x400).
Measurements of hormone concentrations
Hormone assays were conducted by immunochemistry (Architect, Abbott Diagnostics, Mississauga, Canada) and were available for each of the 241 blood samples evaluated in this study.
Statistical analyses
The mixed linear regression model, an extension of repeated measures ANOVA and linear regression, was used to estimate mean profiles and to test whether there were differences in the profiles between the two groups. Profiles were modeled using straight lines, piecewise linear splines, quadratics, or cubic functions, and likelihood ratio tests were used to determine which of these shapes provided an adequate fit to the data while remaining parsimonious. The mixed model methodology correctly adjusts for correlations that exist between measurements made on the same woman. It also corrects for potential biases that can be caused by differing profile lengths and missing data points. We used likelihood ratio tests to test for differences in the shapes of the mean profiles between women who subsequently became pregnant and those who did not.
For some analyses, the residuals were highly skewed, and in these cases, the dependent variable was transformed using the log (base e) transformation. Analyses were performed using SigmaStat and SAS (SAS Institute, Inc., Cary, NC). All P values reported are from mixed model likelihood ratio tests unless otherwise stated.
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Results |
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The number of blood samples collected before ET varied considerably between individuals, with one to six pre-ET samples. However, the average number of pre-ET samples did not differ between the groups (P = 0.78, by t test). There was no difference in the number or the quality of embryos transferred between pregnant and nonpregnant groups (Table 2).
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FET cohort.
The data were grouped into those who became pregnant (n = 3; Fig. 1) and those who did not become pregnant (n = 15). The nonpregnant group also includes data from one woman who had a biochemical pregnancy (shown as a heavier line). The pattern of mean adhesion over time differed significantly (P = 0.008) between women who subsequently had successful pregnancy compared with those who did not. This increase was blocked in the presence of function-blocking antibody to L-selectin (data not shown). Specifically, in the pregnant group, the mean log number of adherent cells showed a steady increase from ET d –3, peaking on the day of ET, followed by a decrease back to baseline levels at 18 d after ovulation (LD18). In the group of women who were not successful in becoming pregnant or maintaining implantation, the mean log number of adherent cells remained constant over the study interval. From the mean log adhesion data, a model of the predicted pattern of adhesion between those who became pregnant and those who did not was constructed (Fig. 1E). There was no significant difference in the average number of blood samples analyzed in the pregnant vs. nonpregnant groups (P = 0.271, by t test).
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, three of the 14 women who were diagnosed with female factor as the underlying cause of infertility became pregnant. No woman classified with male factor or idiopathic cause became pregnant in the FET group. The relationship between pregnancy outcome and underlying cause of infertility was not statistically significant (P = 1.0, by Fisher’s exact test).
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). The nonpregnant group includes three women who exhibited biochemical pregnancy (shown as heavier lines). We found that women who became clinically pregnant showed an increase in mean log adhesion that peaked on the day of OPU, followed by a decline that continued to LD18. Again, this increase was not evident when lymphocytes were pretreated with a function-blocking antibody to L-selectin (data not shown). In women who were unsuccessful in becoming pregnant or sustaining an implanting embryo, log adhesion remained constant. This difference in adhesion profiles was statistically significant (P = 0.0002; Fig. 1F). Although there is some reason to believe that ova mature faster in more fertile women, there were no differences in the number of blood samples analyzed per woman in the pregnant vs. nonpregnant groups (P = 0.0967, by t test).
In the women who underwent COH, two of the eight women classified with female factor infertility became pregnant, as did both women with idiopathic presentation and three of five women with male factor as the underlying cause of infertility (Table 4). However, the relationship between diagnosis and pregnancy outcome was not significant (P = 0.3102, by Fisher’s exact test).
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FET cohort.
Figure 2 shows the percentage of the total lymphocyte population within the lymphocyte gate that expresses CD56dim and CD56bright at each sample point for each subject in each of the cohorts. There was no difference between the percentage of total lymphocytes occupied in the CD56bright subset in pregnant (0.432%) and nonpregnant (0.385%) women (P = 0.7162) or in the rates of change over time (P = 0.0718). Thus, the percentage of CD56bright cells was not diagnostic of pregnancy success. No difference was found in the percentage of CD56dim cells between the pregnant (13.43%) and nonpregnant (11.77%) groups (P = 0.7546) or in the rates of change over time (P = 0.6069) despite large fluctuations in individual profiles. Moreover, there were no differences in CD4-, CD8-, CD19-, CD33-, or CD34-expressing lymphocytes among the groups (data not shown).
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Analysis of hormone data
FET cohort.
The plots in Fig. 3 depict mean hormone measurements within each treatment group. Cubic functions were necessary to adequately model E2 and LH up to the day of the LH surge. There were no differences detected in E2 or LH concentrations between pregnant and nonpregnant groups (P = 0.6842 and P = 0.5905 respectively). Furthermore, there were no differences in P4 values at ET (P = 0.071, by Mann-Whitney rank-sum test). E2 was not significantly associated with the percentage of CD56bright cells in either pregnant (P = 0.5618) or nonpregnant (P = 0.5062) groups or with the percentage of CD56dim cells in either pregnant (P = 0.0884) or nonpregnant (P = 0.5281) groups.
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The hormone levels of the women who underwent COH are shown in Fig. 3. Cubic and quadratic functions were necessary to adequately fit the E2 and P4 values over time. There were no differences in E2 levels (P = 0.3894) or P4 values (P = 0.1701) between those who became pregnant and those who did not. In addition, there was no correlation between E2 and the percentage of CD56bright in either the pregnant group (P = 0.9675) or the nonpregnant group (P = 0.1824). Similarly, there was no correlation between E2 and the percentage of CD56dim in either the pregnant group (P = 0.2482) or the nonpregnant group (P = 0.7556).
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Discussion |
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, there is considerable variability in the number of adherent cells among women. However, there is a consistent pattern over time for each individual woman who became pregnant, namely, a rise in adhesion, followed by a decline to below baseline levels by LD18. This pattern was also seen in two of the 26 subjects who did not become pregnant (neither had a biochemical pregnancy). This finding reinforces our previous observations in mouse models, which indicated that parallel and coordinated changes in adhesive function occurred in both circulating lymphocytes and uterine endothelial cells during pregnancy (17). In this study, because we measure only the lymphocyte response, because it is not possible to assess uterine endothelial cell responses in women attempting pregnancy, we surmise that in these two women, endothelial cells did not respond adequately to hormonal signals. The changes in lymphocyte adhesiveness occur before an embryo is present and thus are completely independent of a pregnancy or embryonic factors. We speculate that these changes are associated with endometrial products involved in implantation and could be predictive of successful treatment outcome. Because we had previously determined that NK cell homing potential increased at ovulation (21), the first objective of this study was to determine whether conception extended the interval for homing potential. Adhesion was studied in infertile women not receiving hormone treatment (FET) because their cycles are closely monitored clinically. We did not find that very early pregnancy was associated with a state of elevated adhesion. Indeed, a drop in adhesion occurred between ET and LD18 in pregnant women. This outcome is consistent with our previous experiments in which we observed that adhesion was reduced after ovulation in fertile donors, and that culture of lymphocytes from male donors in the presence of P4 reduced adhesion (21). In contrast, consistent changes in adhesion profile were not detected in the women who did not become pregnant or support early implanting embryos, and the predicted profile for this group was constant over the test period. At ET, the estimated mean adhesion was higher in the pregnant group by exp(1.09) or 2.78 cells/high-power field.
The second objective of this study was to determine whether the administration of exogenous hormones to infertile women modified the adhesive potential of their CD56+ blood cells. In the COH group, adhesion in the pregnant cohort peaked on the day of OPU (1 d after hCG), which differed from that of the pregnant outcome group of the FET cohort, which peaked at ET (3 d after LH). The women in the COH group who did not become pregnant showed no consistent pattern in adhesion profiles, and the estimated mean profile in this group remained unchanged throughout the test period. Thus, the observed differences in lymphocyte behavior were between women who became pregnant and those who did not, rather than between women conceiving during a natural cycle and those conceiving during a hormonally medicated cycle. This suggests that circulating CD56+ cells and dNK cell progenitors are not significantly altered in function by current clinical protocols for COH.
Our definition of pregnancy is based on clinical pregnancy; that is, an hCG level of 5 IU/liter or greater on LD18, followed by detection of a fetal heart beat or gestational sac on ultrasound on LD40. If the level was less than 50 IU, the test was repeated 2 d later. In a viable early stage pregnancy, hCG values double every 2 d. A positive LD18 hCG value that cannot be confirmed by the presence of fetal heart beat or gestational sac on ultrasound on LD40 was classified as a biochemical pregnancy. The LD18 serum hCG concentrations in the pregnant groups ranged from 170-2604 IU/liter, with an average of 860 IU/liter. All but four patients in the nonpregnant groups had a negative hCG test on LD18. Of the single FET patient and the three COH nonpregnant patients with positive LD18 hCG values, only one had what appeared to be a viable pregnancy (54 IU/liter), which was lost by LD40. The adhesion data of these biochemical pregnancy patients is highlighted in Fig. 1 by the presence of heavier lines. The data for the patient with an LD18 hCG level of 54 is represented by the solid line in Fig. 1D, and the others are shown as dashed lines. Because each of these patients was defined as having a biochemical, rather than a clinical, pregnancy, they were grouped with the nonpregnant women. The adhesion data of these patients more closely resembles those of the nonpregnant cohorts than the pregnant groups, suggesting viable embryos, but a nonsustaining maternal environment.
There were no differences in embryo quality, as assessed by morphological criteria, or in hormone levels between those who became pregnant and those who did not. Measurements of soluble human leukocyte antigen G were not available. Furthermore, we were not able to correlate the etiology of infertility to outcome. For both groups of pregnant women, we observed lower levels of CD56+ cell adhesion on LD18 and higher levels on LD40. This suggests that the initial phase of homing to the uterus is triggered by periovulatory conditions during the menstrual cycle (before ET) and that a second wave of homing occurs about wk 6 of pregnancy. Because peak numbers of dNK cells are found at 6–12 wk of pregnancy (7, 22), these data are consistent with a scenario in which embryo-induced factors such as CXCL12 (stromal cell-derived factor-1) attract an additional contingent of CD56+ dNK precursor cells, over a longer period of elevated lymphocyte-endothelial cell interactions, to replenish the rapidly proliferating uterine population.
In both FET and COH groups, not only did the pattern of adhesive change seen in women who became pregnant differ from that in women who did not, but the mean number of adhering cells was higher. Yamamoto et al. (24) reported that the ratio of peripheral CD56dim to CD56bright cells was higher in women with recurrent spontaneous abortion (RSA) and that these women had a reduced number of uterine CD56+ cells. This observation is related to earlier studies, which show that proportions of CD56dim cells in peripheral blood are higher in infertile women and women with RSA than in fertile women and that cytotoxicity of NK cells is enhanced in women with RSA. However, the proportion of NK cell subtypes did not correlate to cytotoxic effector capability (25, 26). It has also been suggested that successful pregnancy is associated with a peripheral CD56+ population of less than 12% (26). Our data differ from these reports. We found no difference in peripheral CD56dim or CD56bright cell proportions between the pregnant and nonpregnant groups of FET patients, but we did detect a decrease over time in the percentage of CD56dim cells (from a mean of 30.89% on ET d 6 to 11.61% on LD40) in COH patients who became pregnant. In addition, we found that the percentage of CD56bright cells was significantly higher in the group that became pregnant in the COH cohort. Thus, neither the number of peripheral NK cells nor their relative proportions appear to be associated with pregnancy success in natural cycles, but in hormone-treated cycles, higher levels of CD56bright cells are associated with pregnancy success.
In fertile cycles, CD56bright cells responded to rising E2, and in the FET group to LH, by enhanced adhesiveness, but in nonfertile cycles this reaction did not occur. Increased adhesiveness could be due to either a direct hormonal effect on a subset of cells or other unidentified soluble factors up-regulated by E2 or LH, which then act on adhesion molecules expressed by NK cells. The latter seems more probable, because we have been unable to detect hormone receptors (ER, ERß, P4 receptor, or LH receptor) on CD56+ cells isolated from blood using quantitative PCR (our manuscript in preparation).
We demonstrate here that peripheral blood CD56+ cells in fertile cycles differ in homing potential from those of infertile cycles. These results obtained indicate that alterations in NK cell adhesion during the ovulation/ET period is a mandatory, but not sufficient, prerequisite for establishing pregnancy. These studies provide a potential measure of the state of uterine readiness for implantation; however, larger studies are required to rigorously evaluate the predictive value of this assay. These studies may also provide a rare measure of immune/uterine synchronization with conceptus development, because the study of periimplantation uterine endothelium in women is difficult. More precise definition of the molecular basis of these phenomena, coordinated in blood NK cells, endothelium, decidua, and perhaps trophoblast (27), is required to advance issues of patient classification and infertility diagnostics.
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Acknowledgments |
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Footnotes |
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First Published Online March 22, 2005
Abbreviations: CCR, C-C chemokine receptor; COH, controlled ovarian hyperstimulation; CXCL, CXC chemokine ligand; CXCR, CXC chemokine receptor; DB, decidua basalis; dNK cell, decidual natural killer cell; E2, 17ß-estradiol; ER, estrogen receptor; ET, embryo transfer; FET, frozen embryo transfer; FITC, fluorescein isothiocyanate; gd, gestation day; hCG, human chorionic gonadotropin; IFN-, interferon-; LD, luteal day; NK cell, natural killer cell; OPU, oocyte pickup; P4, progesterone; PE, phycoerythrin; RSA, recurrent spontaneous abortion; uNK cell, uterine natural killer cell.
Received September 24, 2004.
Accepted March 15, 2005.
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contributes to the normalcy of murine pregnancy. Biol Reprod 61:493–502 contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J Exp Med 192:259–270This article has been cited by other articles:
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C. G. Peralta, V. K. Han, J. Horrocks, B. A. Croy, and M. J. van den Heuvel CD56bright cells increase expression of {alpha}4 integrin at ovulation in fertile cycles J. Leukoc. Biol., October 1, 2008; 84(4): 1065 - 1074. [Abstract] [Full Text] [PDF]
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 S. D. Burke, H. Dong, A. D. Hazan, and B. A. Croy Aberrant Endometrial Features of Pregnancy in Diabetic NOD Mice Diabetes, December 1, 2007; 56(12): 2919 - 2926. [Abstract] [Full Text] [PDF]
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