Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease

Abstract

CD4 ؉ CD25 ؉ regulatory T cells (T regs ) have been shown to inhibit graft-versus-host disease (GVHD) in murine models, and this suppression was mediated by T regs expressing the lymphoid homing molecule L-selectin. Here, we demonstrate that T regs lacking expression of the chemokine receptor CCR5 were far less effective in preventing lethality from GVHD. Survival of irradiated recipient animals given transplants supplemented with CCR5 ؊/؊ T regs was significantly decreased, and GVHD scores were enhanced compared with animals receiving wild-type (WT) T regs . CCR5 ؊/؊ T regs were functional in suppressing T-cell proliferation in vitro and ex vivo. However, although the accumulation of T regs within lymphoid tissues during the first week after transplantation was not dependent on CCR5, the lack of function of CCR5 ؊/؊ T regs correlated with impaired accumulation of these cells in the liver, lung, spleen, and mesenteric lymph node, more than one week after transplantation. These data are the first to definitively demonstrate a requirement for CCR5 in T reg function, and indicate that in addition to their previously defined role in inhibiting effector T-cell expansion in lymphoid tissues during GVHD, later recruitment of T regs to both lymphoid tissues and GVHD target organs is important in their ability to prolong survival after allogeneic bone marrow transplantation. ( IntroductionAcute graft-versus-host disease (GVHD) is a severe and potentially fatal complication of allogeneic bone marrow transplantation (allo-BMT). Acute GVHD is caused by mature donor T cells that recognize alloantigens presented initially by host antigen presenting cells (APCs). 1,2 Our group has demonstrated that the accumulation of donor T cells during the peritransplantation period takes place primarily in lymphoid tissues, followed by recruitment to parenchymal tissues such as the gastrointestinal (GI) tract, liver, lung, and skin. 3 We and others have recently demonstrated that eliminating expression of the chemokine receptor CCR5 from donor T cells in an experimental GVHD model resulted in exacerbated GVHD and increased T-cell infiltration of the liver and lung in lethally irradiated recipient animals. 4,5 These data suggested that the primary role for CCR5 during GVHD in conditioned transplant recipients is not to direct effector-cell recruitment as originally hypothesized, but to down-modulate target organ inflammation.Chemokines are predominantly 8-kDa to 12-kDa chemotactic proteins, which bind a family of 7-transmembrane-spanning G protein-coupled receptors, and function primarily in leukocyte migration (reviewed in Moser et al 6 ). The chemokine receptor CCR5 is expressed on activated T helper-1/T cytotoxic-1 (T H 1/ T C 1) T cells, natural killer (NK) cells, macrophages, and dendritic cells. 7 The ligands for this receptor, CCL3, CCL4, and CCL5, are expressed at sites of inflammation during acute GVHD. 4,[8][9][10][11] CCR5 may play a role in directing effector cells to sites of inflammation. [12][13][14][15] Interestingly howeve...

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

“…On the other hand, inflammation-seeking, effector/memory-like Treg are specialized to control ongoing immune responses directly within the inflammatory environment. Indeed, expression of trafficking receptors such as selectin ligands and chemokine receptors on effector/memorylike Treg subsets critically influences their in vivo suppressive capacity in inflammation [13,[15][16][17], suggesting that appropriate localization is indispensable for Treg function [2].…”

Induction of organ‐selective CD4+ regulatory T cell homing

“…Indeed, we and others have recently demonstrated that expression of certain HR such as selectin ligands and chemokine receptors on Treg subsets critically influences their suppressive capacity in vivo [43][44][45][46], suggesting that appropriate localization is indispensable for Treg function [30]. Although HR known from conventional T cells can also be found on Treg, it is presently unknown, if non-overlapping, organselective Treg subsets exist and how their trafficking is regulated.…”