LAUSR

T recipients, especially those with underdosed immunosuppressive therapy, are at risk of posttransplant antibody development against HLA antigens of the organ donor. The de novo donor-specific antibodies (DSA) can be harmful to the transplant recipient because they are able to induce severe antibody-mediated rejection (AMR) and AMR-associated graft loss. The immune mechanisms that regulate the production of DSA are not well understood. In this issue, Zimmerer et al present C-X-C chemokine receptor type 5 (CXCR5)interferon-gamma (IFN-γ)cluster of differentiation 8(CD8)T lymphocytes as a potential inhibitor of DSA formation in renal transplant recipients. This concept represents a new mechanism involved in the regulation of de novo DSA formation. Zimmerer et al were the first to describe in 2010 the phenotype and mechanism of antibody-suppressor CXCR5IFN-γCD8 lymphocytes in mice that negatively regulate humoral responses in hepatocyte transplant recipients. This cell subset also downregulates combined T helper (Th)1 and Th2-driven alloantibody formation after islet or skin transplantation in mice. The murine alloprimed CD8 T cells eliminate alloprimed IgG B cells through perforinand Fas ligand-dependent mechanisms and downregulate alloprimed CD4 T cells. In a recent study with mice, the authors showed that the expression of CXCR5 by antigen-primed CD8 T cells is critical for the function of antibody-suppressor CD8 T cells. CXCR5 is a chemokine receptor important for germinal center homing. In a mouse model, alloantibody suppression by adoptively transferred CXCR5IFN-γCD8 T cells into transplant recipients was accompanied by a reduction of B cells and cytokine-expressing CD4 follicular B helper T cells in the germinal center. Usually, CXCR5CD8 lymphocytes maintain a cytotoxic capacity that helps to control viral infection, tumor growth inhibition, or promotion of inflammation and autoimmune responses, as reviewed by Valentine and Hoyer. However, a regulatory role of CXCR5CD8 T cells was also described by Miles et al and Chu et al. CXCR5CD8 cells were able to inhibit IgG production by B cells during ex vivo HIV infection and inhibited plasmablast cell differentiation in a dose-dependent manner using a coculture assay with B cells, follicular B helper T, and CXCR5CD8 T cells. In the present study published in this issue, Zimmerer et al tried to find a homolog of the murine antibody-suppressor CXCR5IFN-γCD8 lymphocytes in renal transplant patients. They attempted to confirm their hypothesis that DSA-positive patients have an activated immune system that lacks regulation by CD8 antibody-suppressor cells. The authors investigated 95 first-time human kidney transplant recipients with 1-year follow-up. Peripheral blood CD4 and CD8 lymphocyte subsets as well as pretransplant and de novo developed posttransplant DSA were investigated prospectively and serially immediately pretransplant and at 1, 3, 6, 9, and 12 months posttransplant. Blood lymphocytes were separated and peripheral blood mononuclear cell fractions were stored frozen, thawed, stimulated with phorbol 12-myristate 13-acetate/Ionomycin and analyzed using flow cytometry. All patients were negative for DSA before transplantation and homogenous with respect to induction and maintenance immunosuppression. Twenty-three recipients (24.2%) developed de novo DSA within 1-year posttransplant directed against HLA class I or class II that were associated with higher hospital readmissions, higher rate of acute rejection, and inferior kidney transplant survival. The authors observed that during the first posttransplant year, IFN-γCD8 and CXCR5IFN-γCD8 T lymphocytes were consistently lower in DSA-positive than DSA-negative patients and that there was a significant difference in these CD8 lymphocyte subsets between DSA-positive and DSAnegative patients already before transplantation at day 0. There was no impact of infections or intensified rejection treatment on CD8 subset quantities. However, blood samples were obtained in 3-month intervals, and individual fluctuations might have gone undetectable in the present study. A preliminary statistical analysis of 9 DSA-positive with and 14 DSA-positive patients without acute rejection or graft loss showed that there was no significant difference in peripheral Th1 or Th2 CD4 T-cell subsets or IFN-γ or CXCR5IFNγ CD8 T-cell subsets among both patient groups. Furthermore, the authors observed that DSA-positive recipients showed more interleukin-4CD4 T cells and Received 16 January 2020.