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Science 5 December 2008:
Vol. 322. no. 5907, pp. 1562 - 1565
DOI: 10.1126/science.1164511
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Reports

Maternal Alloantigens Promote the Development of Tolerogenic Fetal Regulatory T Cells in Utero

Jeff E. Mold,1,2 Jakob Michaëlsson,3 Trevor D. Burt,1,4 Marcus O. Muench,5 Karen P. Beckerman,6* Michael P. Busch,5 Tzong-Hae Lee,5 Douglas F. Nixon,1 Joseph M. McCune1{dagger}

As the immune system develops, T cells are selected or regulated to become tolerant of self antigens and reactive against foreign antigens. In mice, the induction of such tolerance is thought to be attributable to the deletion of self-reactive cells. Here, we show that the human fetal immune system takes advantage of an additional mechanism: the generation of regulatory T cells (Tregs) that suppress fetal immune responses. We find that substantial numbers of maternal cells cross the placenta to reside in fetal lymph nodes, inducing the development of CD4+CD25highFoxP3+ Tregs that suppress fetal antimaternal immunity and persist at least until early adulthood. These findings reveal a form of antigen-specific tolerance in humans, induced in utero and probably active in regulating immune responses after birth.

1 Division of Experimental Medicine, Department of Medicine, University of California at San Francisco (UCSF), San Francisco, CA 94110, USA.
2 Biomedical Sciences Graduate Program, UCSF, San Francisco, CA 94143, USA.
3 Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, 141 86, Stockholm, Sweden.
4 Department of Pediatrics, Division of Neonatology, UCSF, San Francisco, CA 94143, USA.
5 Blood Systems Research Institute and Department of Laboratory Medicine, UCSF, San Francisco, CA 94118, USA.
6 Department of Obstetrics, Gynecology, and Reproductive Sciences, UCSF, San Francisco, CA 94143, USA.

* Present address: Albert Einstein College of Medicine, Bronx, NY 10461, USA.

{dagger} To whom correspondence should be addressed. E-mail: mike.mccune{at}ucsf.edu

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Tolerance in renal transplantation: is mixed chimerism the missing link?.
S. Janes, P. Dhaliwal, and K. Wood (2009)
Nephrol. Dial. Transplant. 24, 1726-1729
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A Lesson in Tolerance -- Maternal Instruction to Fetal Cells.
W. J. Burlingham (2009)
N. Engl. J. Med. 360, 1355-1357
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