MacDonald, Kelli P.A.2; Le Texier, Laetitia2; Zhang, Ping2; Morris, Helen2; Kuns, Rachel D.2; Lineburg, Katie E.2; Leveque, Lucie2; Don, Alistair L.2; Markey, Kate A.2; Vuckovic, Slavica3; Bagger, Frederik Otzen5; Boyle, Glen M.2; Blazar, Bruce R.6; Hill, Geoffrey R.2
1 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet2 QIMR Berghofer Medical Research Institute3 unknown4 University of Minnesota5 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet6 University of Minnesota
The majority of allogeneic stem cell transplants are currently undertaken using G-CSF mobilized peripheral blood stem cells. G-CSF has diverse biological effects on a broad range of cells and IL-10 is a key regulator of many of these effects. Using mixed radiation chimeras in which the hematopoietic or nonhematopoietic compartments were wild-type, IL-10(-/-), G-CSFR(-/-), or combinations thereof we demonstrated that the attenuation of alloreactive T cell responses after G-CSF mobilization required direct signaling of the T cell by both G-CSF and IL-10. IL-10 was generated principally by radio-resistant tissue, and was not required to be produced by T cells. G-CSF mobilization significantly modulated the transcription profile of CD4(+)CD25(+) regulatory T cells, promoted their expansion in the donor and recipient and their depletion significantly increased graft-versus-host disease (GVHD). In contrast, stem cell mobilization with the CXCR4 antagonist AMD3100 did not alter the donor T cell's ability to induce acute GVHD. These studies provide an explanation for the effects of G-CSF on T cell function and demonstrate that IL-10 is required to license regulatory function but T cell production of IL-10 is not itself required for the attenuation GVHD. Although administration of CXCR4 antagonists is an efficient means of stem cell mobilization, this fails to evoke the immunomodulatory effects seen during G-CSF mobilization. These data provide a compelling rationale for considering the immunological benefits of G-CSF in selecting mobilization protocols for allogeneic stem cell transplantation.
Journal of Immunology, 2014, Vol 192, Issue 7, p. 3180-3189