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International Immunology Advance Access published online on August 30, 2006
International Immunology, doi:10.1093/intimm/dxl084
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received December 1, 2005
Accepted August 3, 2006

Article

An MHC-linked locus modulates thymic differentiation of CD4+CD25+Foxp3+ regulatory T lymphocytes

Julie Tellier 1, Joost P. M. van Meerwijk 2 *, and Paola Romagnoli 1

1 Tolerance and Autoimmunity section, Centre de Physiopathologie de Toulouse Purpan, Institut National de la Santé et de la Recherche Médicale (INSERM) U563; University Paul Sabatier and IFR 30, Institut Claude de Preval, Toulouse, France
2 Tolerance and Autoimmunity section, Centre de Physiopathologie de Toulouse Purpan, Institut National de la Santé et de la Recherche Médicale (INSERM) U563; University Paul Sabatier and IFR 30, Institut Claude de Preval, Toulouse, France; Institut Universitaire de France and Faculty of life-sciences (UFR-SVT), University Paul Sabatier, Toulouse, France

* To whom correspondence should be addressed.
Joost P. M. van Meerwijk, E-mail: joost.van-meerwijk{at}toulouse.inserm.fr


  Abstract

CD4+CD25+Foxp3+ regulatory T lymphocytes are crucial for maintenance of immunological tolerance to self and innocuous non-self, are known to modulate immunity to tumors and infectious agents and can induce transplantation tolerance. Surprisingly, only a single genetic polymorphism is known to modulate regulatory T cell (Treg) development in the thymus, leading to a lethal autoimmune disorder. Here, we show that considerably different levels of Tregs are found in the thymi of distinct common laboratory mouse strains. We demonstrate that distinct levels of phenotypically and functionally identical Tregs develop with similar kinetics in the studied mice, that the responsible locus acts in a thymocyte-intrinsic manner and that levels of thymic Foxp3+ Tregs correlate to those found in the periphery. Using several congenic mouse strains, we mapped one of the at least two genetic loci capable of quantitatively modulating thymic Treg development to a ≤2.2 Mb region telomeric to the MHC. Our data indicate that polymorphic genes closely linked to the MHC locus substantially modulate differentiation of Tregs. Identification of responsible genes should help in understanding the mechanisms involved in commitment to the Treg lineage as well as selection of these cells in the thymus.

Keywords: T cells; thymus; tolerance.
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