Role for granulocyte colony-stimulating factor in the generation of human T regulatory type 1 cells.
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-10 (IL-10) and transforming growth factor-beta1 (TGF-beta1) by T cells from healthy volunteer donors treated with recombinant human G-CSF. Highly purified CD4(+) T cells obtained before and after G-CSF administration (pre-G and post-G, respectively) were activated using the allogeneic mixed leukocyte reaction. Post-G CD4(+) T cells produced high levels of IL-10 but undetectable levels of IL-2 and IL-4, whereas the level of TGF-beta1 release was comparable to that of pre-G CD4(+) T cells. Notably, post-G CD4(+) T cells proliferated poorly in response to alloantigens and to recall antigens and suppressed the proliferation of autologous CD4(+) T cells in a cell contact-independent and an antigen-nonspecific manner. TGF-beta1 and IL-10 were not dispensable for post-G CD4(+) T cells to mediate suppression, as shown by neutralization studies. Compared with pre-G CD4(+) T cells, alloantigen-activated post-G CD4(+) T cells preferentially expressed 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 a peculiar cytokine production profile (IL-10(++)TGF-beta1(+)IL-2(low/-)IL-4(low/-)), an intrinsic low proliferative capacity, and a 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.
Rutella
Sergio
S
Departments of Hematology and Gynecology, Catholic University Medical School, Rome, and the Laboratory of Clinical Pathology and Microbiology, IRCCS San Gallicano, Rome, Italy. sergiorutella@tin.it
Pierelli
Luca
L
Bonanno
Giuseppina
G
Sica
Simona
S
Ameglio
Franco
F
Capoluongo
Ettore
E
Mariotti
Andrea
A
Scambia
Giovanni
G
d'Onofrio
Giuseppe
G
Leone
Giuseppe
G
D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002453:Cell Cycle / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D017931:DNA Primers; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D008213:Lymphocyte Activation; D008297:Male; D019707:Receptors, Chemokine / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics
D015703:Antigens, CD; D016207:Cytokines; D017931:DNA Primers; D019707:Receptors, Chemokine; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor