Conversion of Alloantigen-Specific CD8+ T Cell Anergy to CD8+ T Cell Priming through In Vivo Ligation of Glucocorticoid-Induced TNF Receptor

Abstract

In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced TNF receptor (GITR) in a murine model of systemic lupus erythematosus-like chronic graft-vs-host disease (cGVHD). A single dose of DTA-1 inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis, typical symptoms of cGVHD. DTA-1-treated mice showed clinical and pathological signs of acute GVHD (aGVHD), such as lymphopenia, loss of body weight, increase of donor cell engraftment, and intestinal damage, indicating that DTA-1 shifted cGVHD toward aGVHD. The conversion of cGVHD to aGVHD occurred because DTA-1 prevented donor CD8+ T cell anergy. Functionally active donor CD8+ T cells produced high levels of IFN-γ and had an elevated CTL activity against host Ags. In in vitro MLR, anergic responder CD8+ T cells were generated, and DTA-1 stimulated the activation of these anergic CD8+ T cells. We further confirmed in vivo that donor CD8+ T cells, but not donor CD4+ T cells, were responsible for the DTA-1-mediated conversion of cGVHD to aGVHD. These results indicate that donor CD8+ T cell anergy is a restriction factor in the development of aGVHD and that in vivo ligation of GITR prevents CD8+ T cell anergy by activating donor CD8+ T cells that otherwise become anergic. In sum, our data suggest GITR as an important costimulatory molecule regulating cGVHD vs aGVHD and as a target for therapeutic intervention in a variety of related diseases.

Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

“…+ T-cell anergy by CD4 + CD25 + regulatory T cells in chronic graft-versus-host disease GITR, the induction of anergy in CD8 + T cells can be prevented in transplant models (Wilcox et al, 2004;Kim et al, 2006a).…”

“…It is interesting in this context that transgenic donor CD8 + T cells with allospecificity against a host MHC alloantigen become anergic shortly after massive deletion (Zhang et al, 1996;Bimalangshu et al, 1999). In cGVHD, donor CD8 + T cells follow a similar fate-most donor CD8 + T cells are deleted and the residual apoptosisresistant cells become anergic (Kim et al, 2006a). Even though anergic CD8 + T cells are different from regulatory T cells (Treg cells) in that proliferation of anergic CD8 + T cells are impaired after exposure to Ags, anergic CD8 + T cells share many features of Treg cells such as secretion of IL-10 and inhibition of other Ag-specific T cells (Zhang et al, 1996;Bimalangshu et al, 1999).…”

“…In contrast to aGVHD, cGVHD is caused by alloreactive donor CD4 + T cells that hyperactivate host B cells, resulting in breaking self-tolerance (Morris et al, 1990;Rus et al, 1995). Donor CD8 + T cells of DBA/2 origin fall into anergy in BDF1 recipients (Kim et al, 2006a). Interestingly, breaking of donor CD8 + T cell-anergy results in the conversion of a chronic form of GVHD to an acute form, indicating that donor CD8 + T cell-anergy is a restriction factor for the development of cGVHD (Pals et al, 1984;Via et al, 1987;Kim et al, 2006a).…”

“…Donor CD8 + T cells of DBA/2 origin fall into anergy in BDF1 recipients (Kim et al, 2006a). Interestingly, breaking of donor CD8 + T cell-anergy results in the conversion of a chronic form of GVHD to an acute form, indicating that donor CD8 + T cell-anergy is a restriction factor for the development of cGVHD (Pals et al, 1984;Via et al, 1987;Kim et al, 2006a). At present, it is not known what controls CD8 + T-cell anergy in cGVHD.…”

Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy

“…[22][23][24][25][26][27][28][29][30] Although some studies indicate that GITR ligation in mice leads to abrogation of Treg-mediated suppression, 27,44 others show that the function of GITR may be due to direct costimulation and expansion of T-cell subsets 23,26,33,[45][46][47] possibly rendering the effector T cells resistant to Treg suppression. 28,32,39,48 Consistent with these published results, our data suggest that anti-GITRsecreting DC synergize with antigen-presenting DC to stimulate and expand T-cell subsets (Figure 4a) and enhance effector T-cell function (Figure 4b).…”