Cord blood nucleated cells induce delayed T cell alloreactivity.

Cord blood (CB) mononuclear cells (MNCs) can be transplanted in HLA mismatched recipients with limited graft rejection or graft-versus-host disease (GVHD). Previous studies have shown that naive T cells and hyporesponsive dendritic cells are largely represented in CB. Data presented here demonstrate that CB MNCs are unable to stimulate allogeneic T cell proliferative or cytotoxic responses in standard in vitro assays. However, a suppressive effect of CB MNCs was ruled out because purified CD34(+) cells or CD14(+) monocytes stimulated T cell responses that were not inhibited by add-back of CB MNCs. The lack of antigen-presenting cell (APC) activity of CB MNCs in primary mixed lymphocyte culture (MLC) did not induce allogeneic T cell anergy. In fact, rechallenge of T cells with CB CD34(+) cells, or immature monocyte-derived dendritic cells (iMo-DCs) in secondary MLC induced potent T cell proliferative responses. A delayed APC activity of CB MNCs was observed after stimulation with irradiated allogeneic T cells for 6 days, likely because of the upregulation of CD86 and HLA-DR on CB cells. Cytotoxic lymphocytes (CTL) were generated after stimulation of blood T cells with CB MNCs for 4 weeks or CB-derived iMo-DCs for 1 week. Concomitant stimulation of T cells with CB iMo-DC obtained from 2 CB units resulted in the generation of CTLs specific for each CB, independently of the CB:CB cell ratio. These data suggest that the APC activity of CB cells possibly increases posttransplant, and may contribute to delayed graft rejection and/or acute and chronic GVHD.

Allogeneic T cells induce rapid CD34+ cell differentiation into CD11c+CD86+ cells with direct and indirect antigen-presenting function.

Dendritic cells (DCs) derive from CD34+ cells or monocytes and stimulate alloimmune responses in transplantation. We hypothesized that the interaction between CD34+ cells and allogeneic T cells would influence the function of hematopoietic stem cells (HSCs). Cord blood (CB) CD34+ cells proliferated briskly in response to allogeneic, but not autologous, T cells when mixed with irradiated T cells for 6 days in vitro. This proliferation was significantly inhibited by an anti-HLA class II monoclonal antibody (mAb), by an anti-TNFalpha mAb, or by CTLA4-Ig. Allogeneic T cells induced the differentiation of CD34+ progenitors into cells with the morphology of dendritic monocytic precursors and characterized by the expression of HLA-DR, CD86, CD40, CD14, and CD11c, due to an endogenous release of TNFalpha. Cotransplantation of CD34+ cells with allogeneic T cells into nonobese diabetic-severe combined immunodeficiency (NOD/SCID) mice resulted in a greater engraftment of myeloid CD1c+ dendritic cells compared with cotransplantation with autologous T cells. In vitro, CD34+ cell-derived antigen-presenting cells (APCs) were functionally capable of both direct and indirect presentation of alloantigens. Based on these findings, we hypothesize that in HSC transplantation the initial cross talk between allogeneic T cells and CD34+ cells may result in the increased generation of APCs that can present host alloantigens and possibly contribute to the development of graft-versus-host disease.