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

Abstract

In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8 + T cells rapidly fall into anergy to host cells, while donor CD4 + T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8 + T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8 + T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4 + CD25 + regulatory T cells (T reg cells) are critical in maintaining the donor CD8 + T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of T reg cells in determining cGVHD versus aGVHD.

Characterization of in vitro antimurine thymocyte globulin–induced regulatory T cells that inhibit graft-versus-host disease in vivo

“…72 Additional studies have demonstrated that depletion of regulatory cells under conditions of chronic GVHD converts the disease to the acute form, coincident with expansion of CD8 ϩ T cells, suggesting that regulatory cells preferentially suppress CD8 ϩ T-cell responses. 46 Our results are consistent with these data because transfer of mATG-induced regulatory cells inhibits acute GVHD and is associated with suppressed CD8 ϩ T-cell expansion. Thus, regulatory cell induction and/or transfer might be particularly useful in disease settings mediated or contributed to by CD8 ϩ T cells.…”

“…Because cytotoxic CD8 ϩ T cells are important for the direct tissue damage and acute manifestations of GVHD under conditions of disparities in both MHC class I and II loci, 44,45 the depletion of or suppression of the expansion and/or activity of CD8 ϩ T cells is beneficial in reducing disease symptoms. [44][45][46] These data indicate that the transfer of in vitro mATG-treated cells results in inhibition of allogeneic CD8 ϩ T-cell expansion. There were no detectable effects of the mATG-treated splenocytes on CD4 ϩ T-cell percentages in the blood at any time point, however, it remains possible that depressed functional activity of CD4 T cells is responsible for limiting the CD8 ϩ T-cell expansion and decreased disease manifes- Figure 6.…”

Breaking of CD8+ T Cell Tolerance through In Vivo Ligation of CD40 Results in Inhibition of Chronic Graft-versus-Host Disease and Complete Donor Cell Engraftment

“…Interestingly, depletion of donor CD4 ϩ T cells, regardless of whether anti-CD40 mAb or control Ig was administered, induced significant levels of host cell deletion, in particular, host B cells but not donor cell engraftment. This phenomenon might occur because of the absence of donor regulatory CD4 ϩ T cells that regulate donor CD8 ϩ T cell anergy in cGVHD (39). As expected, basal levels of autoantibody were produced in mice that received donor cells depleted of CD4 ϩ T cells (Table III).…”

The Role of Animal Models in the Study of Hematopoietic Stem Cell Transplantation and GvHD: A Historical Overview

“…Thus, there is a notion that the frequencies of donor alloreactive CD8 + T cells may determine whether aGvHD or cGvHD develops. For example, CD8 + T cell anergy can shift the responses from an aGvHD to an SLE-like cGvHD (194, 213). Although CD8 + T cells are not necessary to induce cGvHD, they infiltrate skin and intestines where they contribute to the observed pathology (214).…”