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

摘要

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 development in the thymus, leading to a lethal autoimmune disorder. Here we show that considerably different levels of regulatory T cells are found in thymi of distinct common laboratory mouse strains. We demonstrate that distinct levels of phenotypically and functionally identical regulatory T cells develop with similar kinetics in the studied mice, that the responsible locus acts in a thymocyte intrinsic manner, and that levels of thymic Foxp3⁺ regulatory T cells 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 regulatory T cell development to a ≤ 2.2 Mbp region telomeric to the MHC. Our data indicate that polymorphic genes closely linked to the MHC locus substantially modulate differentiation of regulatory T cells. Identification of responsible genes should help in understanding mechanisms involved in commitment to the regulatory T cell lineage as well as selection of these cells in the thymus.