Another potential mechanism that may describe the differential effect

of auto and allospecific Treg cells on donor engraftment in this model, is related to the ability of Treg cells to regulate natural killer (NK) cell activity [34]. NK cells are known to be important contributors of rejection of parental bone marrow transplants in semi-allogeneic transplant settings [35], which is attributed to NK-cell activation upon recognition of cells “missing self” MHC Class I expression. Treg cells may therefore affect NK-cell targeting of transferred donor cells and also act to inhibit the contribution of activated NK JQ1 chemical structure cells toward driving the alloimmune response. Engrafted donor T cells from allospecific Treg-cell-treated animals retained the capacity to react against 3rd party alloantigens, but were unresponsive to either autologous or recipient alloantigens, confirming that allospecific Treg cells mediated donor-specific

regulation in vivo, which was sufficient to simultaneously prevent donor T-cell alloreactivity and recipient autoimmunity. Allospecific Treg cells may therefore be more beneficial for long-term clinical use than autospecific or polyclonal Treg cells, as they provide the additional benefit of permitting engraftment of donor T cells with the capacity to respond to foreign antigens, Akt inhibitor which therefore have the potential to mediate graft-versus-leukemic activity [36]. Of particular interest was the observation that although donor T cells were hyporesponsive to autologous-MHC antigen and recipient alloantigen, no CD4+CD25+FoxP3 Treg cells were detected within engrafted donor cells (not shown), implying that allospecific Treg-cell application may have mediated the deletion of autoreactive and alloreactive

donor T-cell clones, or have induced infectious tolerance [37]. The pathophysiology of cGVHD is multifaceted, involving components of both alloreactivity Phosphatidylethanolamine N-methyltransferase and autoimmunity, whereby alloreactive donor T cells initiate the immune processes leading to cGVHD, which stimulate a cascade of autoimmune-directed responses by the recipient [12, 38]. In the cGVHD model used in this study, the resulting B-cell hyperactivity and autoantibody generation, which is characteristic of lupus [39], would have occurred through the inappropriate provision of T-cell help by alloreactive donor T cells [40]. Our findings confirm that a combination of alloimmunity and dysregulated autoimmune reactivity both play a critical role in the progression of cGVHD, and more importantly highlight that control of alloreactivity may present an optimised strategy for preventing cGVHD autoimmunity.