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Antibody-suppressor CD8+ T Cells Require CXCR5

Zimmerer, Jason M. PhD1; Ringwald, Bryce A. BS2; Elzein, Steven M. BS2; Avila, Christina L. MPH1; Warren, Robert T.1; Abdel-Rasoul, Mahmoud MS, MPH3; Bumgardner, Ginny L. MD, PhD1

doi: 10.1097/TP.0000000000002683
Original Basic Science—General
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Background. We previously reported the novel activity of alloprimed CD8+ T cells that suppress posttransplant alloantibody production. The purpose of the study is to investigate the expression and role of CXCR5 on antibody-suppressor CD8+ T-cell function.

Methods. C57BL/6 mice were transplanted with FVB/N hepatocytes. Alloprimed CD8+ T cells were retrieved on day 7 from hepatocyte transplant recipients. Unsorted or flow-sorted (CXCR5+CXCR3 and CXCR3+CXCR5) alloprimed CD8+ T-cell subsets were analyzed for in vitro cytotoxicity and capacity to inhibit in vivo alloantibody production following adoptive transfer into C57BL/6 or high alloantibody-producing CD8 knock out (KO) hepatocyte transplant recipients. Alloantibody titer was assessed in CD8 KO mice reconstituted with naive CD8+ T cells retrieved from C57BL/6, CXCR5 KO, or CXCR3 KO mice. Antibody suppression by ovalbumin (OVA)-primed monoclonal OVA-specific t-cell receptor transgenic CD8+ T cells (OT-I) CXCR5+ or CXCR3+ CD8+ T-cell subsets was also investigated.

Results. Alloprimed CXCR5+CXCR3CD8+ T cells mediated in vitro cytotoxicity of alloprimed “self” B cells, while CXCR3+CXCR5CD8+ T cells did not. Only flow-sorted alloprimed CXCR5+CXCR3CD8+ T cells (not flow-sorted alloprimed CXCR3+CXCR5CD8+ T cells) suppressed alloantibody production and enhanced graft survival when transferred into transplant recipients. Unlike CD8+ T cells from wild-type or CXCR3 KO mice, CD8+ T cells from CXCR5 KO mice do not develop alloantibody-suppressor function. Similarly, only flow-sorted CXCR5+CXCR3 (and not CXCR3+CXCR5) OVA-primed OT-I CD8+ T cells mediated in vivo suppression of anti-OVA antibody production.

Conclusions. These data support the conclusion that expression of CXCR5 by antigen-primed CD8+ T cells is critical for the function of antibody-suppressor CD8+ T cells.

1 Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH.

2 Medical Student Research Program, The Ohio State University College of Medicine, Columbus, OH.

3 Center for Biostatistics, The Ohio State University, Columbus, OH.

Received 23 July 2018. Revision received 31 December 2018.

Accepted 1 January 2019.

The authors declare no conflicts of interest.

J.M.Z. and G.L.B. participated in research design. J.M.Z., B.A.R., and G.L.B. participated in writing of the paper. J.M.Z., S.M.E., M.A-R., and G.L.B. participated in data analysis. J.M.Z., B.A.R., S.M.E., C.L.A., and R.T.W. participated in performance of the research.

This work was supported by a grant from the National Institutes of Health grants AI083456 (G.L.B.), CA016058, the OSU Division of Transplant Surgery, and the OSU College of Medicine.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Ginny L. Bumgardner, Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, 395 W. 12th Avenue, 166 Faculty Tower, Columbus, OH. (ginny.bumgardner@osumc.edu).

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