Regulatory T cells (Tregs) fulfill a central role in immune regulation. We reported previously that the integrin αEβ7 discriminates distinct subsets of murine CD4+ regulatory T cells. Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. αE −CD25+ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues. In contrast, αE-positive subsets (CD25+ and CD25−) displayed an effector/memory phenotype expressing high levels of E/P-selectin–binding ligands, multiple adhesion molecules as well as receptors for inflammatory chemokines, allowing efficient migration into inflamed sites. Accordingly, αE-expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis.

During ageing thymic function declines and is unable to meet the demand for peripheral T helper (Th) cell replenishment. Therefore, population maintenance of naive Th cells must be at least partly peripherally based. Such peripheral postthymic expansion of recent thymic emigrants (RTEs) during ageing consequently should lead to loss or dilution of T cell receptor excision circles (TRECs) from a subset of naive T cells. We have identified two subsets of naive Th cells in human adult peripheral blood characterized by a striking unequal content of TRECs, indicating different peripheral proliferative histories. TRECs are highly enriched in peripheral naive CD45RA+ Th cells coexpressing CD31 compared with peripheral naive CD45RA+ Th cells lacking CD31 expression, in which TRECs can hardly be detected. Furthermore we show that CD31−CD45RA+ Th cells account for increasing percentages of the naive peripheral Th cell pool during ageing but retain phenotypic and functional features of naive Th cells. As CD31 is lost upon T cell receptor (TCR) engagement in vitro, we hypothesize that TCR triggering is a prerequisite for homeostatically driven peripheral postthymic expansion of human naive RTEs. We describe here the identification of peripherally expanded naive Th cells in human adult blood characterized by the loss of CD31 expression and a highly reduced TREC content.

IntroductionCompelling evidence indicates that regulatory T (Treg) cells play an important role in the maintenance of immune tolerance to selfand foreign antigens (Ags). [1][2][3] In mice and humans, various subsets of T lymphocytes that have the ability to down-regulate the proliferation of autoimmune effector cells have been isolated. [4][5][6] CD4 ϩ CD25 ϩ T cells are the most extensively studied Treg cells. Eliminating CD4 ϩ CD25 ϩ T cells from the periphery of mice leads to the development of systemic autoimmune diseases, and adding them back can ameliorate experimentally induced autoimmune diseases and graft-versus-host disease after allogeneic bone marrow transplantation. 7,8 Other Treg cells, including CD4 ϩ CD45Rb low , CD4 ϩ DX5 ϩ T cells, 9 CD8 ϩ T cells, 10 T-cell receptor (TCR)␥␦ ϩ cells, 11 and TCR␣␤ ϩ CD3 ϩ CD4 Ϫ CD8 Ϫ double-negative (DN) T cells 12,13 have also been demonstrated to have a potent role in down-regulating immune responses.The majority of peripheral TCR␣␤ ϩ CD3 ϩ T cells in normal mice express either CD4 or CD8 molecules. However, approximately 1% to 3% of peripheral CD3 ϩ T cells express TCR␣␤ but neither CD4 nor CD8 and are thus DN T cells. Strober et al 14 were the first to describe a natural suppressor activity of DN T cells that was not major histocompatibility complex (MHC) restricted. In humans and mice, DN T cells are detected in lymphoid and nonlymphoid tissues (for a review, see Reimann 15 ). Clonal or oligoclonal expansion of DN T cells in humans has been reported in healthy individuals 16 and in patients with either autoimmune diseases 15,17 or combined immunodeficiency with features of autologous graft-versus-host disease. 18 Zhang and colleagues 12 were the first to identify and characterize Ag-specific DN Treg cells. They initially demonstrated, in mice, that DN Treg cells have a unique phenotype that makes the DN Treg cells different from any previously described T cell. They further demonstrated that (1) DN Treg cells, as a novel subset of Treg cells, can specifically down-regulate immune responses toward allo-Ags both in vitro and in vivo 12 ; (2) both primary activated and cloned DN Treg cells can specifically kill activated CD4 ϩ and CD8 ϩ T cells with the same TCR specificity 12,19,20 ; and (3) infusion of in vitro-activated DN Treg cells leads to significant prolongation of donor-specific skin 12 and heart graft survival. 21 Others have shown that DN Treg cells also play an immune regulatory role in autoimmune and infectious diseases. 13 In vitro studies have identified a unique mechanism by which DN Treg cells mediate an Ag-specific suppression of syngeneic responder cells. Studies showed that DN Treg cells can use their TCR to acquire allo-MHC peptides from antigen-presenting cells (APCs) and use them to specifically trap and kill CD4 ϩ or CD8 ϩ T cells that recognize the same allo-MHC peptides through a process that requires cell-to-cell contact and Fas/FasL interaction. 12 Although it has been evident that the DN Treg cell population constitutes a unique li...