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Prepublished online as a Blood First Edition Paper on June 7, 2002; DOI 10.1182/blood-2001-12-0291.
Submitted December 27, 2001
Accepted May 21, 2002
A role for granulocyte colony-stimulating factor (G-CSF) in the generation of human T regulatory type 1 (Tr1) cells
Sergio Rutella*, Luca Pierelli, Giuseppina Bonanno, Simona Sica, Franco Ameglio, Ettore Capoluongo, Andrea Mariotti, Giovanni Scambia, Giuseppe d'Onofrio, and Giuseppe Leone
Department of Hematology, Catholic University School of Medicine, Rome, Italy
Department of Gynecology, Catholic University School of Medicine, Rome, Italy
Laboratory of Clinical Pathology and Microbiology, IRCCS San Gallicano, Rome, Italy
* Corresponding author; email: sergiorutella{at}tin.it.
Granulocyte colony-stimulating factor (G-CSF) may affect T-cell homeostasis by multiple mechanisms, inducing polarization of cytokine secretion, inhibition of T-cell proliferation and enhancement of T-cell apoptosis. We analyzed the production of interleukin (IL)-10 and transforming growth factor-ß1 (TGF-ß1) by T cells from healthy volunteer donors treated with recombinant human G-CSF. Highly purified CD4+ T cells obtained prior to (preG) and after G-CSF administration (postG) were activated using the allogeneic mixed leukocyte reaction. PostG CD4+ T cells produced high levels of IL-10 but undetectable levels of IL-2 and IL-4, whereas the level of TGF-ß1 release was comparable with that of preG CD4+ T cells. Notably, postG CD4+ T cells proliferated poorly in response to allo-antigens as well as to recall antigens and suppressed the proliferation of autologous CD4+ T cells in cell contact-independent and antigen-nonspecific manner. TGF-ß1 and IL-10 were not dispensable for postG CD4+ T cells to mediate suppression, as shown by neutralization studies. Compared with preG CD4+ T cells, allo-antigen activated postG CD4+ T cells expressed preferentially markers associated with memory T cells, in conjunction with reduced levels of CD28 and CD62L. Collectively, these data demonstrate that CD4+ T cells exposed to G-CSF in vivo acquire the properties of T regulatory (Tr) cells once triggered in vitro through the T-cell receptor, including 1) peculiar cytokine production profile (IL-10++TGF-ß1+IL-2low/-IL-4low/-), 2) intrinsic low proliferative capacity and 3) contact-independent suppression of antigen-driven proliferation. Tr cells generated ex vivo after exposure to G-CSF might be clinically relevant for transplantation medicine and for the treatment of human immune-mediated diseases.
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