Transplantation

Oral

Distinct Alloimmune Stimulatory Profile of Monocyte-derived Dendritic Cells and cd40l-stimulated B Cells

Friday, June 16
6:15 PM - 7:30 PM

Donor-derived allogeneic B cells have been used to measure alloimmune responses in transplant patients, and to expand alloantigen-reactive regulatory T cells (Tregs) that are being tested clinically to induce tolerance and control rejection in liver and kidney transplant patients. However, dendritic cells (DCs) are potent antigen-presenting cells (APCs) that also contribute to alloimmune responses. Therefore, we compared the T cell-stimulating capacity of human mature monocyte-derived DCs (mDCs), differentiated from CD14+ blood monocytes, to CD40L-stimulated B cells (sBcs). In mixed PBMC and purified T cell cultures, mDCs promoted more robust proliferation of allogeneic Tregs, conventional CD4+ T cells (Tconv), and CD8+ T cells compared to sBcs, correlating with mDCs expressing higher levels of HLA and costimulatory molecules compared to sBcs. Both mDCs and sBcs produced large amounts of the chemokines CCL22 and CCL5, whereas sBcs also produced a high amount of CXCL10. Neither APC type produced much TNFα, IL-1α, IL-1β, IL-6, IL-12p70, or IL-23 that can destabilize Tregs. Additionally, mDCs, but not sBcs, produced IL-1R antagonist. TCR sequencing analysis showed that TCR repertoires of sBc- and mDC-expanded Tregs were diverse. The two repertoires had less than 20% overlap, suggesting the two APC types may stimulate distinct repertoires of alloantigen-reactive T cells. Additional experiments are ongoing to determine repertoires of mDC- and sBc-stimulated Tconv and CD8+ T cells and their relatedness to graft-infiltrating T cells in kidney rejection biopsies. These results will provide important information on which APC type provides more accurate recall of pathogenic and tolerogenic alloimmune responses in transplant patients.

Linda M. Lee

Postdoctoral Scholar
University of California San Francisco

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    Hong Zhang

    Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh

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      Karim Lee

      University of California, San Francisco

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        Angus W. Thomson

        Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh

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          Qizhi Tang

          Director, Transplantation Research Laboratory
          UCSF

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