Expansion of CD4+CD25+and FOXP3+ Regulatory T Cells during the Follicular Phase of the Menstrual Cycle: Implications for Human Reproduction

Abstract

Regulatory T cells (Tregs) are thought to affect the severity of various infectious and autoimmune diseases. The incidence of autoimmune disease is higher in fertile women than in men. Thus, we investigated whether Treg numbers were modulated during the menstrual cycle by sex hormones. In fertile nonpregnant women, we detected an expansion of CD4+CD25+FOXP3+ Tregs in the late follicular phase of the menstrual cycle. This increase was tightly correlated with serum levels of estradiol and was followed by a dramatic decrease in Treg numbers at the luteal phase. Women who have had recurrent spontaneous abortions (RSA) showed similarly low numbers of Tregs at both the follicular and luteal phases, comparable to numbers we observed in postmenopausal women. In addition to decreased numbers, Tregs from women with RSA were also functionally deficient, as higher numbers were required to exert a similar magnitude of suppression to CD4+CD25+FOXP3+ cells from fertile women. Consequently, reproductive failure might result from the inability of Tregs in women with RSA to expand during the preimplantatory phase combined with their lower functional capacity. Additionally, the modulation of Treg numbers we observed in fertile women suggests that the stage of the menstrual cycle should be taken into account when Treg numbers are investigated clinically.

Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17β-estradiol

“…Further, since pregnancy is a situation of alloantigen "awareness", our in vitro system with low grade of TCR stimulation seems more physiologically representative of pregnancy. Recently, Tregs and levels of 17β-estradiol, but not progesterone, were shown to correlate during the menstrual cycle (41). However, as both 17β-estradiol and progesterone increase dramatically during pregnancy (33) and the effects of 17β-estradiol seem to be concentration-dependent (42), the influence of these hormones might well be different during pregnancy.…”

MECHANISMS IN ENDOCRINOLOGY: Thyroid and polycystic ovary syndrome

“…Conversely, estrogens were reported to enhance Treg formation (84). Accordingly, the number of Tregs was shown to decrease during the luteal phase and to increase during the late follicular phase (86). Pregnancy is associated with several adjustments in the immune system in order to tolerate the fetus, predominantly with a shift from a Th1 cytokine profile to a Th2 cytokine profile (87,88).…”

Adaptive Immune Responses During Pregnancy

“…16 The therapeutic potential of Treg for pregnancy was described by us shortly thereafter in a model of disturbed tolerance during pregnancy. 17 It is nowadays known that Treg fluctuate in number in blood and uterus during the receptive phase of the menstrual or estrus cycle, 35 (A. Teles et al, unpublished data), which is interpreted as a requisite for pregnancy establishment further underlined by the fact that impaired increase or diminished suppressive capacity is associated with infertility or pregnancy complications. [36][37][38] As it was discussed already, seminal fluid is pivotal in expanding Treg 39 and local application of TGF-b in the mice had the same effect.…”