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Expansion of CD4⁺CD25⁺and FOXP3⁺ Regulatory T Cells during the Follicular Phase of the Menstrual Cycle: Implications for Human Reproduction¹

Lourdes Arruvito^*, Marianela Sanz^*, Alison H. Banham and Leonardo Fainboim^2,*,

^* Immunogenetics Laboratory, "José de San Martín" Clinical Hospital, and Department of Microbiology, Parasitology and Immunology, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina; and Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina (PIP 5456). A.H.B. is supported by the Leukaemia Research Fund.

² Address correspondence and reprint requests to Dr. Leonardo Fainboim, División Inmunogenética, Hospital de Clínicas "José de San Martín", Facultad de Medicina, Universidad de Buenos Aires Avenida Córdoba 2351 (1120), Buenos Aires, Argentina. E-mail address: lfainboim{at}hospitaldeclinicas.uba.ar

³ Abbreviations used in this paper: Treg, regulatory T cell; FOXP3, factor forkhead box P3; RSA, recurrent spontaneous abortion; SI, suppressive index; E2, estradiol; PTEN, phosphatase and tensin homolog deleted on chromosome 10.

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