Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

Abstract

Apoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-bdependent donor CD4 þ CD25 þ T-cell expansion. Such cells have a regulatory phenotype (CD62L high and intracellular CTLA-4 þ ), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover.

Sirolimus enhances the effect of apoptotic cell infusion on hematopoietic engraftment and tolerance induction

“…apoptotic cell infusion facilitates engraftmentFwhen administrated with allogeneic bone marrow (BM) transplantsFwithout triggering autoimmunity or GvHD. 5 This effect relies on a transforming growth factor (TGF)-b-dependent mechanism. 5 Furthermore, i.v.…”

“…5 This effect relies on a transforming growth factor (TGF)-b-dependent mechanism. 5 Furthermore, i.v. apoptotic cell infusion is associated with a CD4 þ CD25 þ regulatory T cell (Treg) increase early after BM transplantation (BMT; days 6 and 8).…”

“…apoptotic cell infusion is associated with a CD4 þ CD25 þ regulatory T cell (Treg) increase early after BM transplantation (BMT; days 6 and 8). 5 These Tregs expressed high levels of Foxp3 transcripts and exerted a potent ex vivo suppressive activity through a cell-to-cell contact mechanism. 5 Nonetheless, such results 5 were achieved without administration of immunosuppressive drugs.…”

“…5 These Tregs expressed high levels of Foxp3 transcripts and exerted a potent ex vivo suppressive activity through a cell-to-cell contact mechanism. 5 Nonetheless, such results 5 were achieved without administration of immunosuppressive drugs. In human settings, immunosuppressive treatments are mandatory, at least during the early phase of AHCT, until tolerance is fully established.…”

Infusion of UVB-treated splenic stromal cells induces suppression of β cell antigen-specific T cell responses in NOD mice

“…It has been documented that steady state apoptotic cells phagocytosed by dendritic cells can render dendritic cells to be tolerogenic and subsequently tolerize CD4+ T cells and CD8+ T cells through direct antigen presentation and antigen cross-presentation, respectively [6]. It has also been shown that steady state apoptotic cells can trigger phagocytes to secrete immunosuppressive cytokines, such as IL-10 and TGF-β [7,8], which in turn facilitate the development of regulatory T cells [9]. Due to this unique relationship between apoptotic cells and immune tolerance, apoptotic cells have been employed with success in inducing immune tolerance to allogeneic antigens [10] and other exogenous antigens [11].…”