Ex Vivo-Expanded CD4+CD25+ Immunoregulatory T Cells Prevent Graft-versus-Host-Disease by Inhibiting Activation/Differentiation of Pathogenic T Cells

Abstract

CD4+CD25+ immunoregulatory T cells (Tregs) can be administered to inhibit graft-vs-host disease (GVHD) while preserving graft-vs-leukemia activity after allogeneic bone marrow transplantation in mice. Preclinical studies suggest that it is necessary to infuse as many Tregs as conventional donor T cells to achieve a clinical effect on GVHD. Thus, it would be necessary to expand Tregs ex vivo before transplantation. Two strategies have been proposed: expansion of Tregs stimulated by anti-CD3/CD28-coated microbeads for polyclonal activation or by host-type allogeneic APCs for selecting Tregs specific for host Ags. In this study, we describe the mechanisms by which ex vivo-expanded Tregs act on donor T cells to prevent GVHD in mice. We demonstrate that expanded Tregs strongly inhibited the division, expansion, and differentiation of donor T cells, with a more pronounced effect with Tregs specific for host Ags. These latter cells permit the efficient and durable control of GVHD and favor immune reconstitution.

Reciprocal generation of Th1/Th17 and Treg cells by B1 and B2 B cells

“…Previous efforts to generate T reg cells included retroviral transduction of CD4 + T cells [20], polyclonal expansion of nT reg cells [21], and induction of iT reg cells using DC [22]. We report here that conventional B2 cells efficiently convert Foxp3 -T cells into iT reg cells, at frequencies greater than seen with DC (data not shown).…”

Regulatory and Effector T Cell Activation Levels Are Prime Determinants of In Vivo Immune Regulation

“…CD25 ϩ and CD25 Ϫ cells were prepared as previously described (28). Briefly, brachial, axillary, cervical, and inguinal LN and spleen were mechanically dissociated.…”

Isolation of human antigen‐specific regulatory T cells with high suppressive function

“…Therefore, polyspecific CD4 + CD25 high cells are currently being evaluated after stem cell transplantation [13]. However, under nonlymphopenic conditions as seen in patients with autoimmune diseases or in patients after organ transplantation, polyspecific Treg cells have so far been largely ineffective in controlling immune responses [5,14,15]. Instead, we and others showed that only Ag-specific Treg cells recognizing Ags from the affected tissue can control autoimmunity under nonlymphopenic conditions [14][15][16][17].…”

“…In addition, chronic nonspecific immunosuppression causes renal dysfunction and predisposes patients to infections and increased Correspondence: Dr. Elmar Jaeckel e-mail: Jaeckel.Elmar@mh-hannover.de risk of malignancies [1]. Innate and adaptive immune responses can be controlled by Treg cells, thereby offering new therapeutic options after organ transplantation [2][3][4][5][6]. CD4 + CD25 high FOXP3 + Treg cells have been shown to be of major importance in allospecific tolerance in animal models and to influence donor-specific immune responses in transplant patients [7][8][9][10].…”

“…Therefore, polyspecific CD4 + CD25 high cells are currently being evaluated after stem cell transplantation [13]. However, under nonlymphopenic conditions as seen in patients with autoimmune diseases or in patients after organ transplantation, polyspecific Treg cells have so far been largely ineffective in controlling immune responses [5,14,15] [24], and CD137 (4-1BB) [25] were described as Treg-cell activation markers after polyspecific Treg-cell activation.In this manuscript, we demonstrated for the first time that LAP and GARP can be used for the isolation of highly pure alloantigenspecific Treg cells. In addition, we showed that CD40 ligand (CD154) is not expressed on naïve and activated Treg cells.…”