Work

279: Modification of T cell Responses by Stem Cell Mobilization Requires Direct Signalling of the T cell by G-CSF and IL-10

Year: 2008

Type: article

Abstract: G-CSF is increasingly described as a therapy for a diverse range of diseases and although the mechanisms involved remain unclear, IL-10 is thought to play a key role as a regulatory effector molecule. Since G-CSF is used as a stem cell mobilizing agent, we generated mixed radiation chimeras as stem cell donors in which haematopoietic or non-haematopoietic compartments were wild-type (WT), IL-10-/-, G-CSFR-/- or combinations thereof. T cells from donors mobilized with G-CSF had impaired ability to induce GVHD only when the haematopoietic compartment was G-CSFR competent, whereas G-CSFR signalling within the non-haematopoietic compartment was irrelevant. Furthermore, we demonstrate that the attenuation of T cell function requires direct signalling of the T cell by G-CSF. Using G-CSF mobilized IL-10-/- radiation chimeras as SCT donors, when the non-haematopoietic compartment was WT, T cells had impaired ability to induce GVHD regardless of their ability to secrete IL-10. In contrast, T cells from chimeric donors in which the non-haematopoietic compartment was IL-10-/- universally induced severe GVHD. Thus, the induction of regulatory T cell function by stem cell mobilization occurs as a consequence of direct T cell signalling by G-CSF in conjunction with IL-10 derived from non-haemopoietic cells. The IL-10 receptor is highly expressed by T cells, particularly CD4+CD25+ regulatory T cells and their depletion from G-CSF treated, but not control grafts, significantly increases graft-versus-host disease (survival 25% v 75% Treg depleted vs non-depleted donors P = 0.002). These studies provide the explanation for the profound effects of G-CSF on T cell function and demonstrate that IL-10 is required to license regulatory function but is not required as an effector molecule.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2007.12.289