Inhibition of vasoactive intestinal polypeptide signaling augments T cell activation by plasmacytoid dendritic cells: implications for cellular immunotherapy

Abstract

Abstract Introduction Murine models of allogeneic hematopoietic stem cell transplant (allo-HSCT) have shown that adding donor plasmacytoid dendritic cell (pDC) to allogeneic HSC and T cell grafts can: 1) augment the graft-versus-leukemia (GvL) activity of T cells by inducing donor Th1 polarization; and 2) limit the subsequent development of graft-versus-host disease (GvHD) through interferon gamma-licensed IDO production by pDC. Vasoactive intestinal polypeptide (VIP) is an immunosuppressive neuropeptide, which may regulate activation of allo-specific T cells, making it a potential target for regulating GvHD and GvL in allo-HSCT. Methods and results We used a model system of indirect presentation by pDC of a I-Ed derived allo-peptide (EaP 52–68) to transgenic T cells expressing the TEa TCR. The effect of blocking VIP signaling from pDC was assessed with VIP-knockout (KO) pDC or by adding a VIP antagonist, VIPhyb. Peptide-primed pDCs from VIP-KO mice increased expression of activation markers (CD69 and CD71) and stimulated TEa T cell proliferation compared with pDCs from WT mice. Similar results were observed in T cells cultured with VIPhyb treated pDCs. T cells proliferated more when cultured with BM VIP-KO pDCs than splenic VIP-KO pDCs. Conclusions These data indicate a novel role for VIP signaling in T cell activation and proliferation in response to indirect antigen presentation. These data support published data on the role of donor pDC in modulating the GvHD activity of T cells and indicate important functional differences in pDC activity according to their source. Ongoing experiments support the immune regulatory effect of VIP on GvHD and GvL in murine allo-HSCT.