Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD

Abstract

IntroductionCD4 ϩ CD25 ϩ regulatory T (Treg) cells are potent modulators of immune responses. We and others have demonstrated that donorderived CD4 ϩ CD25 ϩ Treg cells could suppress lethal acute graft-versus-host disease (aGVHD) in murine models of allogeneic bone marrow transplantation. [1][2][3] In these models, cotransplantation of Treg cells with conventional donor T cells controlled the expansion of alloaggressive T cells in recipient animals, thereby interfering with one of the major events in the initiation phase of aGVHD. 4 Importantly, donor Treg cells did not cause generalized immune paralysis, since the beneficial graft-versus-leukemia/ lymphoma (GVL) effect of donor T cells was maintained. [4][5][6] Modulating alloimmune responses after bone marrow or hematopoietic stem cell transplantation with adoptively transferred donor CD4 ϩ CD25 ϩ Treg cells thus appears as a promising strategy for the prevention or therapy of aGVHD in humans.CD62L (L-selectin) is an important T-cell homing receptor as well as a marker for T-cell development. Naive T cells are CD62L ϩ and interaction of CD62L with its ligands, a group of molecules collectively referred to as peripheral node addressin (PNAd), is crucial for T-cell entry into lymph nodes (LNs) via high endothelial venules. 7 Expression of CD62L is rapidly lost following T-cell receptor engagement, and CD62L Ϫ T cells are thought to be "antigen experienced." There are 2 recent publications demonstrating that CD62L Ϫ donor T cells did not cause GVHD. 8,9 While CD4 ϩ CD62L Ϫ T cells contained a higher fraction of CD4 ϩ CD25 ϩ Treg cells, their inability to induce GVHD was maintained after Treg cell depletion. 8 Nevertheless, these findings called for the reciprocal analysis of the GVHD-regulating capacity of CD62L ϩ and CD62L Ϫ subsets of CD4 ϩ CD25 ϩ Treg cells.Comparing the effects CD4 ϩ CD25 ϩ CD62L ϩ and CD62L Ϫ Treg cell subpopulations in aGVHD was suggested by a second line of investigations. Both subsets had been shown to be equally anergic and suppressive upon polyclonal stimulation in vitro. [10][11][12] Interestingly, we found that in an adoptive transfer model of diabetes into nonobese diabetic-severe combined immunodeficient (NOD-scid) mice, only the CD62L ϩ but not the CD62L Ϫ subset of CD4 ϩ CD25 ϩ Treg cells caused a significant delay of disease onset. 12 In contrast, another group reported recently that both CD62L ϩ and CD62L Ϫ Treg cell subsets were protective in an adoptive transfer model of colitis, 13 suggesting that the inconsistency between in vitro and in vivo experiments in NOD mice may have been related to peculiarities of this mouse strain, which spontaneously develops autoimmune diabetes. In the current study, we used the aGVHD model as an additional in vivo assay for suppressor function in a nonautoimmune disease-prone strain.Using a mouse model for lethal aGVHD induced by major histocompatibility complex (MHC)-mismatched CD4 ϩ CD25 Ϫ T cells, 1 we found that only the CD62L ϩ subpopulation of CD4 ϩ CD25 ϩ T cells protected recipients aga...

Donor double‐negative Treg promote allogeneic mixed chimerism and tolerance

“…Several studies have tried to solve this dilemma. It has been shown that CD4 + Treg from the donor or recipient can control GVHD after BM transplantation [21,[55][56][57][58]. In previous studies, we have found that donor DN-Treg could suppress donor CD8 + T cells, which caused GVHD in a single MHC-mismatched model [32].…”

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

“…Whereas CCR7-deficient naive-like Treg fail to recirculate through LN, resulting in an almost complete abolishment of their ability to inhibit the proliferation of naive T cells at this site, effector/memory-like Treg from CCR7 -/-mice display an increased accumulation in inflamed sites, which was accompanied by an enhanced suppression of the inflammatory reaction. CCR7 expression was predominantly observed on naive-like Treg [3,5,6,11,[31][32][33][34] and CCR7-expressing CD62L high CD25 + CD4 + Treg were found to be very efficient in preventing the development of autoimmunity [5] or in suppressing graft-versus-host disease [35,36]. It was suggested that Treg recirculation through LN mediated by CCR7 and CD62L is a prerequisite to suppress priming of autoreactive effector cells.…”

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

“…Several studies have suggested that differential expression of both CD62L and CD27 on CD4ϩ,CD25 high Treg might be useful in distinguishing Treg subsets by their migratory properties (43)(44)(45). It has been proposed that CD27Ϫ and CD62LϪ Treg are destined to enter the periphery, whereas lymph nodehoming Treg express CD62L and CD27.…”