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Modulation of CD27/CD70 Co-Stimulatory Pathway may Allow for the Generation of a More Potent Human Regulatory T Cell Product for Cell Therapy

Arroyo Hornero, Rebeca; Issa, Fadi; Hester, Joanna; Wood, Kathryn

doi: 10.1097/01.tp.0000520348.63067.34
205.1
Free

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.

Introduction: Regulatory T cell (Treg) therapy is a promising strategy to promote transplant tolerance and aid in the reduction of immunosuppression[1]. This study aims to identify new strategies to increase potency, stability and specificity of human Tregs to produce an effective clinical therapy. Ligation of CD70 to CD27, a costimulatory molecule member of the tumour necrosis factor superfamily, is known to be sufficient and indispensable for the generation of effective and long-term antigen-specific Tcell immunity[2][3][4][5]. In human Tregs, CD27 correlates with suppressive potency after in vitro expansion [6][7]. We hypothesised that CD27/CD70 pathway may have a direct role in the activity of Tregs, and modulation of CD27/CD70 may allow for the generation of Tregs with enhanced suppressive properties.

Methods: TotalTregs (CD4+CD127low/-CD25+) and CD27Tregs (CD4+CD127low/-CD25+CD27+) were sorted from healthy donor PBMCs and expanded in vitro for 14 days using αCD3/αCD28 coated beads in the presence of rhIL-2. Cells were then flow sorted according to CD27 expression and expanded for a further 14 days. Treg phenotype, suppressive function and cytokine production were analysed after expansion by flow cytometry and ELISA.

Results: CD27 expression identified in vitro-expanded human Tregs with regulatory cytokine profile and epigenetically stable Foxp3 expression, studied by demethylation of the TSDR region. Suppressive activity was confined to the CD27+expanded Treg population, and blocking the CD27/CD70 pathway within an in vitro suppression assay potentiated Tcell proliferation and Treg suppression. On ligation of CD27, there was a robust activation and proliferation response in conventional Tcells but high death levels in Tregs, suggesting that CD27 costimulation activates distinct intracellular pathways in these two cell populations.

FIGURE 1

FIGURE 1

Conclusion: Isolation of Tregs by expression of CD27 may facilitate the identification of a more potent and stable Treg product for cellular therapy. All indicates that CD27/CD70 pathway has a direct role in the activity of human Tregs, and its modulation may facilitate the generation of Tregs with enhanced suppressive properties. CD27 costimulation may activate distinct intracellular pathways in conventional and regulatory Tcells, and therefore CD27/CD70 axis could be exploited for regulating the balance between conventional and regulatory T cell responses.

FIGURE 2

FIGURE 2

References:

1. van der Net J.B. Regulatory T cells: first steps of clinical application in solid organ transplantation. Transplant International. 2006; 29(1): 3-11.

2. Hendriks J. CD27 is required for generation and long-term maintenance of T cell immunity. Nature Immunology. 2000; 1(5): 433-440.

3. Arens R. Constitutive CD27/CD70 interaction induces expansion of effector-type T cells and results in IFNgamma-mediated B cell depletion. Immunity. 2001; 15(5): 801-812.

4. Keller A.M. Expression of costimulatory ligand CD70 on steady-state dendritic cells breaks CD8+ T cell tolerance and permits effective immunity. Immunity. 2008; 29(6): 934-946.

5. van Gisbergen K.P. Protective CD8 T cell memory is impaired during chronic CD70-driven costimulation. Journal of Immunology. 2009; 182(9): 5352-5362.

6. Duggleby R.C. CD27 expression discriminates between regulatory and non-regulatory cells after expansion of human peripheral blood CD4+CD25+cells. Blood. 2007; 121(1): 129-139.

7. Imanguli M.M. Comparative analysis of FoxP3(+) regulatory T cells in the target tissues and blood in chronic graft versus host disease. Leukemia. 2014; 28(10): 2016-2027.

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