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Fate of CD8+

Cytotoxic or Suppressor T Cells in Antibody-mediated Rejection in Solid Organ Transplantation?

Dolff, Sebastian MD, PhD1; Wilde, Benjamin MD2; Tebbe, Bastian MD2

doi: 10.1097/TP.0000000000002684
Commentaries
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1 Department of Infectious Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

2 Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Received 18 January 2019. Revision received 13 February 2019.

Accepted 15 February 2019.

The authors declare no conflicts of interest.

All authors drafted the manuscript. S.D. and B.T. created the figure.

Correspondence: Bastian Tebbe, Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. (bastian.tebbe@uk-essen.de).

Solid organ transplantation has overcome major immunologic hurdles to become the success it is today. Significant advances in pretransplant diagnostics and immunosuppressive therapy reduced significantly serious acute rejections and improved graft survival.1 Despite the enormous efforts that were made, 1 key challenge remains unresolved: the prevention of chronic antibody-mediated rejection. T-cell dependent B-cell activation leads to the development of donor-specific antibodies, which have a significant impact on the long-term survival of allografts.

Regulatory T cells (Tregs) are a subpopulation of CD4+ T cells, which act to suppress T-cell activation and differentiation. A suppressed T-cell response indirectly dampens B-cell responses through reduced access to T-cell help. More recently, a novel B-cell population with regulatory capacity has been identified in autoimmune and transplantation models, termed regulatory B cells.2 Regulatory B cells predominantly exert their suppressive function via secretion of interleukin (IL)-10. High-affinity antibodies are generated in germinal centers (GCs), and their production requires the interaction of B cells with specialized CD4+ T-follicular helper cells (Tfh cells).3 Tfh cells express CXCR5, ICOS, and PD-1 and produce IL-21. They are effective drivers of B cell–dependent anti-HLA antibody responses. Excessive antibody responses in the GC are controlled by another distinct population with similarities to the Tfh phenotype but equipped with regulatory function. These T-follicular regulatory cells are of increasing interest in the field of transplantation.3

An interesting but less well-characterized mechanism of B-cell suppression is mediated by CD8+ Foxp3+ Tregs. These cells have been reported to be characteristically CD28, and there is a growing body of evidence that contact-dependent cytokine release plays a pivotal role in their suppressive activity.4,5 CD8+CD103+Tregs have been shown to be expanded by transforming growth factor-β and alloantigen stimulation to produce interferon-γ (IFN-γ) and IL-6,6 and endothelial cell membrane–bound transforming growth factor-β has also been shown to induce the generation of CD8+ Tregs.7 A crucial pathway in the cell-cell interaction has been reported for CD80/CD86-CD28 and PD-1/PD-1L in CD8+ Treg activity. Blocking PD-1 results in allograft skin rejection in a transgenic OT-I system,8 whereas the blockade of CTLA-4 on CD8+ Tregs abolishes the protection of acute graft versus host disease in a mouse model, indicating the importance of direct interaction between CD8+ Tregs and antigen-presenting cells.9

In this issue, Zimmerer et al10 examined the role of CXCR5 in CD8+ T cell–mediated suppression. The authors tested the hypothesis that alloprimed CD8+ T cells inhibit in vivo alloantibody production in a murine hepatocyte transplant model depending on the expression of the lymphoid-homing chemokine receptor CXCR5 (Figure 1). A sophisticated experimental setup was used in which C57BL/6 mice were transplanted with FVB/N hepatocytes and alloprimed CD8+ T cells isolated from spleens of recipients 7 days later and analyzed for the expression of CXCR3 and CXCR5 by flow cytometry. Flow-sorted CXCR3+CXCR5CD8+ T cells and CXCR5+CXCR3CD8+ T cells were cocultured with alloprimed self-IgG1+ B cells in an in vitro cytotoxicity assay. CXCR5+CXCR3CD8+ T cells showed a significantly increased cytotoxic capacity to alloprimed self-IgG1+ B cells as compared with controls, which is consistent with previous studies where cytotoxic function was perforin or Fas mediated.10 To confirm the present findings in vivo, the authors adoptively transferred CXCR5-deficient CD8+ T cells, showing that they had no effect on alloantibody production or IFN-γ expression. Thus, the authors concluded that alloantibody suppression by alloprimed CD8+ T cells is CXCR5 restricted and not secondary to impaired cytokine (in particular, IFN-γ) production.

FIGURE 1

FIGURE 1

Next, the authors showed that the adoptive transfer of CXCR5+CXCR3CD8+ T cells into high alloantibody-producing CD8/ hepatocyte recipients significantly decreased the amount of alloantibody production. This was associated with an improved graft survival. Additionally, antigen-specific antibody-suppressor CD8+ T cells reduced the quantity of 2 important lymphocyte subsets: GC B cells and Tfh cells, both of which are thought to have a major impact on antibody formation.

This innovative study reveals new mechanisms of action of antibody-suppressing CD8+ T cells that include cytotoxic killing of IgG1+ B cells and suppression of the humoral response via the reduction of GC B cells and Tfh cells. However, some questions arise with respect to this phenotypically and functionally novel CD8+ T-cell subset. This study focuses mainly on early autoantibody production, whereas in clinical practice, chronic antibody-mediated rejection represents a major challenge. Additionally, it is unclear whether the reduced numbers of GC B cells and Tfh cells are due to direct killing by CXCR5+CXCR3CD8+ T cells or lack of detection due to their migration to the target allograft. In renal biopsies, tertiary lymphoid structures attract CXCR5+ lymphocytes, therefore, also possibly accounting for the reduction in peripheral circulating numbers. It is likely that cell contact is necessary, but the precise axis remains unclear since classical markers such as ICOSL and PD-1 are not expressed.

In conclusion, this study sheds a light on a new CD8+ T-cell subset, which expresses CXCR5+ and IFN-γ+, and which has promising potential as a future target to modulate humoral immunity in solid organ transplantation.

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