G-CSF as immune regulator in T cells expressing the G-CSF receptor: implications for transplantation and autoimmune diseases.
Results from experimental models, in vitro studies, and clinical data indicate that granulocyte colony-stimulating factor (G-CSF) stimulation alters T-cell function and induces Th2 immune responses. The immune modulatory effect of G-CSF on T cells results in an unexpected low incidence of acute graft-versus-host disease in peripheral stem cell transplantation. However, the underlying mechanism for the reduced reactivity and/or alloreactivity of T cells upon G-CSF treatment is still unknown. In contrast to the general belief that G-CSF acts exclusively on T cells via monocytes and dendritic cells, our results clearly show the expression of the G-CSF receptor in class I- and II- restricted T cells at the single-cell level both in vivo and in vitro. Kinetic studies demonstrate the induction and functional activity of the G-CSF receptor in T cells upon G-CSF exposure. Expression profiling of T cells from G-CSF-treated stem cell donors allowed identification of several immune modulatory genes, which are regulated upon G-CSF administration in vivo (eg, LFA1-alpha, ISGF3-gamma) and that are likely responsible for the reduced reactivity and/or alloreactivity. Most importantly, the induction of GATA-3, the master transcription factor for a Th2 immune response, could be demonstrated in T cells upon G-CSF treatment in vivo accompanied by an increase of spontaneous interleukin-4 secretion. Hence, G-CSF is a strong immune regulator of T cells and a promising therapeutic tool in acute graft-versus-host disease as well as in conditions associated with Th1/Th2 imbalance, such as bone marrow failure syndromes and autoimmune diseases.
Franzke
Anke
A
Department of Hematology and Oncology, Hannover Medical School, Carl-Neuberg-Str 1, D-30623 Hannover, Germany. franzke.anke@mh-hannover.de
Piao
Wenji
W
Lauber
Jörg
J
Gatzlaff
Patricia
P
Könecke
Christian
C
Hansen
Wiebke
W
Schmitt-Thomsen
Angela
A
Hertenstein
Bernd
B
Buer
Jan
J
Ganser
Arnold
A
D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity; D003199:Computer Systems; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D050990:GATA3 Transcription Factor; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000502:physiology*; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014181:Transplantation Immunology
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D012333:RNA, Messenger; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor; D015847:Interleukin-4