Modification of T cell responses by stem cell mobilization requires direct signaling of the T cell by G-CSF and IL-10.

Journal of immunology (Baltimore, Md. : 1950) (2014-03-04)
Kelli P A MacDonald, Laetitia Le Texier, Ping Zhang, Helen Morris, Rachel D Kuns, Katie E Lineburg, Lucie Leveque, Alistair L Don, Kate A Markey, Slavica Vuckovic, Frederik O Bagger, Glen M Boyle, Bruce R Blazar, Geoffrey R Hill
RESUMEN

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.

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AMD3100 octahydrochloride hydrate, ≥97% (NMR), solid

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