Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important hematopoietic growth factor and immune modulator. GM-CSF also has profound effects on the functional activities of various circulating leukocytes. It is produced by a variety of cell types including T cells, macrophages, endothelial cells and fibroblasts upon receiving immune stimuli. Although GM-CSF is produced locally, it can act in a paracrine fashion to recruit circulating neutrophils, monocytes and lymphocytes to enhance their functions in host defense. Recent intensive investigations are centered on the application of GM-CSF as an immune adjuvant for its ability to increase dendritic cell (DC) maturation and function as well as macrophage activity. It is used clinically to treat neutropenia in cancer patients undergoing chemotherapy, in AIDS patients during therapy, and in patients after bone marrow transplantation. Interestingly, the hematopoietic system of GM-CSF-deficient mice appears to be normal; the most significant changes are in some specific T cell responses. Although molecular cloning of GM-CSF was carried out using cDNA library of T cells and it is well known that the T cells produce GM-CSF after activation, there is a lack of systematic investigation of this cytokine in production by T cells and its effect on T cell function. In this article, we will focus mainly on the immunobiology of GM-CSF in T cells.
Identification of GM-CSF
Granulocyte-macrophage colony-stimulating factor (GM-CSF) was first identified in mouse lung tissue-conditioned medium following lipopolysaccharide injection into mice by its ability to stimulate proliferation of mouse bone marrow cells in vitro and generate colonies of both granulocytes and macrophages 1. Much has been learned about the hematopoietic promoting effect of this heavily glycosylated cytokine. GM-CSF stimulates multipotent progenitor cells depending on its concentration, the proliferation of macrophage progenitors at the lowest doses, followed by granulocyte, erythroid, eosinophil, megakaryocyte and multipotent progenitors 2. It also stimulates the differentiation of myeloid leukemic cells 3 and controls eosinophil function in some instances.
The molecular cloning of mouse and human GM-CSF in 1985 was achieved using T cell cDNA libraries 4, 5, which immediately permitted large-scale production of recombinant GM-CSF and extensive in vitro and in vivo studies of the biological activity of this cytokine. GM-CSF is encoded by a 2.5 kb mRNA comprising 4 exons. It is secreted as a monomeric 23 kDa glycosylated small protein. Mature murine GM-CSF has 124 residues and human has 127 residues; both are derived from a precursor containing a signal peptide 6, 7. Murine and human GM-CSF share modest structural homology at the level of the nucleotide (70%) and amino acid (56%) sequences. There is no cross-species receptor binding or biological activity, however. GM-CSF is produced by various cell types including macrophages, mast cells, T cells, fibroblasts and endothelial cells 8, 9, mostly in response to immune activation and cytokines that mediate inflammation. It is present in serum and most tissues, and is also found associated with the extracellular matrix and as an integral membrane protein 10.
The biological activities of GM-CSF are exerted through binding to heteromeric cell-surface receptors that are expressed on monocytes, macrophages, granulocytes, lymphocytes, endothelial cells and alveolar epithelial cells 11. The GM-CSF receptor (GM-CSFR) is composed of a (CDw116; GM-CSFRα) and β (GM-CSFRβc) chains. The βc chain is common to receptors for GM-CSF, IL-3, and IL-5 12. Receptor expression is characterized by low number (20-200/cell) and high affinity (Kd = 20-100 pM) 13, 14. Interestingly, both the α and β chains lack a tyrosine kinase catalytic domain. It has been demonstrated that the βc chain constitutively associates with JAK2. The binding of GM-CSF initiates JAK2 autophosphorylation and post receptor signaling. JAK2 then activates STAT5, and MAPK 15, 16. Non-JAK2 pathways such as the fps/fes pathway have also been implicated in GM-CSF receptor signaling 17, 18.
Regulation of GM-CSF expression
GM-CSF can be produced by a wide variety of tissue types, including fibroblasts, endothelial cells, T cells, macrophages, mesothelial cells, epithelial cells and many types of tumor cells 7. In these cells, bacterial endotoxins and inflammatory cytokines, such as IL-1, IL-6, and TNFα, are potent inducers of GM-CSF 19, 20, 21, 22, 23. The regulation of gene expression is exerted at both transcriptional and posttranscriptional levels 7, 24, 25, 26, 27. The IL-3 and GM-CSF genes are closely linked in the genome and reside within a cluster of cytokine genes 28. Highly inducible expression of both genes at the transcriptional level has been reported. NFAT appears to play a major role in the regulation of GM-CSF expression by the formation of DNase I hypersensitive sites within enhancers 29. The promoter region of the GM-CSF gene contains a variety of positive and negative regulatory regions 30. In addition, it is well established that GM-CSF can be controlled by post-transcriptional mechanisms through the AU-rich element (ARE) in its 3' non-coding region 31, 32, 33, 34. Its expression can be inhibited by IL-10 35, IFNg 36, and IL-4 37, 38. In addition, pharmacological agents such as cyclosporine A 29, 39, 40 and glucocorticoids 41, 42, 43, 44 are strong inhibitors of GM-CSF expression. Under normal conditions, GM-CSF in the circulation is at low or even undetectable levels, which can rise to high levels in response to immune stimuli such as lipopolysaccharide. It should be noted that polymorphonuclear cells can quickly clear GM-CSF 45. However, a significant increase of GM-CSF can be found in local tissues, such as the skin of allergic patients with cutaneous reactions and in the asthmatic lung. Arthritic synovial fluid has also been shown to contain measurable GM-CSF, which is expected to contribute to joint and bone destruction. GM-CSF is produced by T cells after TCR activation along with the appropriate co-stimulatory signals. However, the regulation of GM-CSF expression in T cells is not fully understood. High levels are associated with juvenile chronic myeloid leukemia, acute myeloid leukemia, human T leukemia virus infection 46, 47, 48 and human immunodeficiency virus infections 49.
Overexpression of GM-CSF leads to severe inflammation
In the past 20 years, studies by different approaches have clearly demonstrated that whenever GM-CSF is overexpressed, pathological changes always follow 50. Early studies using mice transgenic for GM-CSF showed that overexpression leads to macrophage accumulation, blindness, and severe damages to various tissues 51. Many cytokines and inflammatory mediators were found to be increased in these mice. GM-CSF overexpression in the stomach leads to autoimmune gastritis 52, 53. When bone marrow cells infected with a retrovirus expressing GM-CSF were transplanted, a lethal myeloproliferative syndrome was induced 54. Adenoviral-mediated GM-CSF gene transfer in the lung also led to severe lung eosinophilia, macrophage expansion and fibrotic reactions 55, 56, 57. This information has led to the hypothesis that GM-CSF may have a central role in promoting sensitization to aeroallergens in polluted air 58, 59. Interestingly, it has been suggested that human GM-CSF polymorphisms are likely asthma determinants 60. Patients with rheumatoid arthritis who are treated with GM-CSF to correct the neutropenia following cancer chemotherapy can suffer worsened rheumatoid disease 61.
Phenotypes of GM-CSF deficient mice
Mice with homozygous deletion of the GM-CSF gene develop normally and show no significant alterations of hematopoiesis up to 12 weeks of age 62. Although most GM-CSF-deficient mice are apparently healthy and fertile, all of them surprisingly develop lung abnormality 62. This coincides with the fact that the very first GM-CSF protein was purified from mouse lung-conditioned medium 1, although very little was investigated about the role of GM-CSF in the lung biology until recently. In the lung of GM-CSF-deficient mice, there is extensive peribronchovascular infiltration of lymphocytes, predominantly B cells. There are numerous large intra-alveolar phagocytic macrophages in the lung. Some mice show lung infections and inflammation involving bacteria or fungi. Some of these features resemble the pathogenesis of human alveolar proteinosis. Therefore, GM-CSF is dispensable for the maintenance of normal levels of the major types of hematopoietic cells and their precursors in blood, marrow, and spleen. Nevertheless, GM-CSF seems to be essential for normal pulmonary physiology and resistance to local infection. When T cells from these mice were examined for their response to antigenic stimulation, it was found that both Th1 and Th2 responses were diminished 63. In fact, administration of anti-GM-CSF antibody was found to reduce the protective immune response to Histoplasma capsulatum, indicating a critical role of GM-CSF in host defense 64. Therefore, GM-CSF is critical in the regulation of T cell immune responses.
GM-CSF and T cells
Immediately after its identification, GM-CSF was suggested to be a proinflammatory cytokine 65. GM-CSF may play a pivotal role in various human inflammatory diseases including rheumatoid arthritis, inflammatory renal disease and inflammatory lung disorders. In a collagen-induced arthritis model, it has been reported that GM-CSF−/− mice develop no disease, and the humoral response to collagen was uncompromised 66. Interestingly, anti-GM-CSF was found to be more effective than anti-TNF in treating rheumatoid arthritis 67. Antibody blockade also revealed that GM-CSF is an important mediator in lung inflammatory models and controls neutrophil and macrophage numbers, as well as TLR-4 (Toll-like receptor 4) expression. More dramatically, intranasal administration of anti-GM-CSF abolished airway hyperresponsiveness and airway inflammation caused by diesel exhaust particulates 68. Similar effects were shown in a murine asthma model 69. Since T cells play a critical role in the pathogenesis of these immune disorders, these observations clearly indicate a role of GM-CSF in the regulation of T cell function.
Both human and mouse GM-CSF were cloned using cDNA from activated T cells 4, 5. It is now generally accepted that resting T cells do not express GM-CSF. While various types of T cells produce GM-CSF upon activation, it is mostly a transient event. During viral infection, both CD4+ and CD8+ T cells are known to produce GM-CSF. Interestingly, CD4+ helper T cells of both the Th1 and Th2 type have been shown to secrete GM-CSF. In recent studies, however, GM-CSF has been found to be critical in the regulation of allergic lung inflammation. Several investigators have shown that T cells readily secrete GM-CSF (200-7000 pg/mL) upon stimulation with anti-CD3 70, 71, 72; its direct effect on T cells remains elusive, however. Since the β chain of the GM-CSF receptor is not expressed by most resting T cells, it is likely that higher than normal levels of GM-CSF are required to trigger the solitary α chain on these cells. This would be consistent with the notion that T cells must be refractory to low levels of GM-CSF in order to avoid over-reaction to the low levels of GM-CSF produced by the innate immune system.
Most of the demonstrated effects of GM-CSF on T cells are believed to be exerted indirectly through antigen-presenting cells (APCs) 63. It has been shown that GM-CSF is critical for DC development and maturation. In fact, in the protocols for in vitro differentiation of DC, GM-CSF is absolutely required. The most studied effects of GM-CSF in the immune system in vivo are in anti-tumor immunity, where the interaction between T cells and the APCs is critical. The outcome of this interaction determines the fate of cancer cells depending on whether a “danger” or a “tolerogenic” signal is received by the DCs. The best anti-tumor effect of GM-CSF is achieved when combined with anti-CTLA4. Interestingly, a recent report showed that GM-CSF converted an autoimmune response into an anti-tumor response by increasing DC density in the draining lymphnode, and increasing the frequency of antigen-specific T cells and the amount of IFN-g secretion 73. Surprisingly, GM-CSF treatment was shown to increase the frequency of CD4+CD25+ T cells with regulatory properties 74, which is related to the high density of MHC class II and B7 molecules on DCs.
GM-CSF not only has the capacity to increase antigen-induced immune responses, but can also alter the Th1/Th2 cytokine balance. It has recently been shown that mice lacking GM-CSF die rapidly from severe necrosis when exposed to an aerosol delivered infection of Mycobacteriuin tuberculosis because of their inability to mount a Th1 response 75. GM-CSF over-expression, however, failed to focus T cells and macrophages into sites of infection, suggesting that uncontrolled expression of GM-CSF leads to defects in cytokine and chemokine regulation. Therefore, excess GM-CSF does not induce an overly Th1 response and very fine control of GM-CSF is needed to fight infections.
In another study, Stampfli et al. 76 demonstrated that adenoviral-based gene transfer of GM-CSF expression promoted a transient increase in IL-4 and IL-5 and an eosinophilic inflammatory response in the lung. They further showed upregulation of DCs and macrophages, as well as the recruitment of CD4+ and CD8+ T cells in the lung. In addition, the CD69 glycoprotein was upregulated, indicative of T cell activation. Alternatively, Barouch et al. 77 studied the effect of an augmented CD4+ T cell response elicited by a bicistronic HIV-1 DNA vaccine expressing gp120 and GM-CSF, reporting greater than 7-fold increases in IFN-γ levels. These results strongly suggest that GM-CSF can stimulate both Th1 and Th2 type responses depending on the conditions. Furthermore, these studies prove that GM-CSF can alter T cell responses directly or indirectly, as well as providing a link between innate and adaptive immunity. Ahlers et al, have shown that complete protection against a recombinant vaccinia virus expressing gp160 can be achieved by the triple combination of GM-CSF, IL-12 and TNF-α, and that GM-CSF enhanced antigen presentation in this study.
In an interesting contrast, a study combining GM-CSF with a DNA vaccine elicited protection against herpes simplex virus infection in the presence of both Th1 and Th2 components. Coinjection of GM-CSF with antigen induced both IL-2 and IFN-γ, and inhibited IL-4 production. This result appears to suggest that GM-CSF promotes Th1 responses, but IgG isotyping showed otherwise as the antibodies were Th2-biased 78, 79. Thus, GM-CSF seems to favor neither Th1 nor Th2 responses exclusively. Others have also reported either Th1 or Th2-biased responses induced by GM-CSF.
Several models of Th1 and Th2 cell differentiation have been proposed, but the molecular mechanisms controlling this process are still unclear. In addition, the exact mechanisms by which cytokines promote differentiation are still debated, and reports of helper T cell differentiation in the absence of signature cytokines add to the confusion. The presence of a “cytokine-adjuvant” such as GM-CSF raises the possibility that helper T cell differentiation or an entire immune response can bypass the need for the driving cytokines. There is little information about what happens to a majority of T cells that are presented with antigen but without the proper cytokine environment to drive differentiation toward classical Th1 or Th2 type cells. Therefore, it would be important to determine whether activated naïve T cells have a positive feedback mechanism utilizing GM-CSF produced by the T cells themselves. Although activated T cells are one of the major sources of GM-CSF, the specific phenotype of T cells that produce GM-CSF has not been identified. T cells have been shown to lose their ability to synthesize GM-CSF during differentiation. Both Th1 and Th2 cytokines, such as IFN-γ, IL-12, IL-4 and IL-10, negatively regulate GM-CSF production, but the function of GM-CSF is not well delineated in activated or differentiated helper T cells. In addition, the physiological relevance of this cytokine especially in helper T cell responses and homeostasis is largely unknown. A diagram depicting the relationship between GM-CSF and T cells is presented in Figure 1.
Early studies showed that GM-CSF acts as an immune adjuvant to drive both humoral and cellular immune responses. GM-CSF has been reported to initiate the proliferation, differentiation and activation of macrophages, neutrophils, various antigen presentation cells, and to some degree, T cells, in addition to several direct immune-stimulatory functions. Clearly, these properties make GM-CSF a potent adjuvant. In fact, injection of irradiated, GM-CSF transfected tumor cells stimulated an intense local inflammatory reaction consisting of DCs, macrophages, and granulocytes 80, 81. The activation and accumulation of such large numbers of APC indicates that GM-CSF functioned to increase tumor antigen presentation. Unlike the type of DC accumulation induced by Flt3-ligand overexpression 82, GM-CSF resulted in much higher levels of protective immunity. It seems that GM-CSF may induce a subset of DCs that are superior for the phagocytosis of particulate material, such as dead tumor cells, and that express more costimulatory molecules. An increase in CD1 expression may also lead to greater activation of NKT cells, which play a crucial role in tumor immunity. Interestingly, tumor cells overexpressing GM-CSF could not induce such a high level of anti-tumor immunity in CD1d-deficient mice 83, 84. In addition to their ability to mobilize and activate DCs and NKT cells, GM-CSF-secreting tumor cells also cause increased production of cytokines such as IL-12 that are required for the activation of CD4+ T cells, which in turn promote cellular immunity and antibody production 85. Other promising approaches include immunization with antigen fused to GM-CSF 86.
Questions about GM-CSF and T cells
There are many examples of the importance of GM-CSF in inflammatory, infectious and autoimmune diseases. Clearly, GM-CSF can affect various cell types and can promote the survival, proliferation, activation and differentiation of various hematopoietic cell lineages, especially macrophages and DCs. Yet, GM-CSF gene-deficiency does not have dramatic effects on steady state numbers of DCs, raising doubts about a distinct role for GM-CSF in DC development and function in vivo. It is well known that many cell types such as lymphocytes, macrophages, fibroblasts, endothelial cells, chondrocytes and smooth muscle cells can make GM-CSF following appropriate stimulation. Very little is known, however, about how GM-CSF production is regulated in the most important producers, the T lymphocytes.
With regard to the link between GM-CSF and T cells, it is odd that we know so little about this important cytokine in this critical population of immune cells. We do not have a clear picture of the conditions and factors that regulate the expression of GM-CSF receptors on T cells. Although activation of CD4+ T cells, CD8+ T cells, and NKT cells leads to the production of GM-CSF, the detailed mechanisms that regulate the expression of this cytokine are poorly understood. While IFN-γ and IL-4 have been shown to inhibit GM-CSF expression, it is unknown whether they account for the transient expression of this cytokine in some T cell populations. Is there a T cell population that is more refractory to downregulation of GM-CSF production by IFN-γ and IL-4? Does GM-CSF produced by T cells play a role regulating the differentiation and function of antigen-presenting cells? Most importantly, can T cells respond directly to GM-CSF? If so, is there a subset difference? Answers to these questions will not only advance our understanding of the basic biology of GM-CSF, but also allow for better clinical applications of this important heterotropic cytokine.
(Granulocyte-macrophage colony-stimulating factor)
(antigen presenting cell)
(tumor necrosis factor)
(type I T helper cell)
(type II T helper cell)
(mitogen-activated protein kinase)
(signal transducer and activator of transcription)
(natural killer cells)
(cytotoxic T-lymphocyte-associated protein 4)
Burgess AW, Camakaris J, Metcalf D . Purification and properties of colony-stimulating factor from mouse lung-conditioned medium. J Biol Chem 1977; 252:1998–2003.
Burgess AW, Metcalf D . The nature and action of granulocyte-macrophage colony stimulating factors. Blood 1980; 56: 947–58.
Nicola NA . Granulocyte colony-stimulating factor and differentiation-induction in myeloid leukemic cells. Int J Cell Cloning 1987; 5:1–15.
Cantrell MA, Anderson D, Cerretti DP, et al. Cloning, sequence, and expression of a human granulocyte/macrophage colony-stimulating factor. Proc Natl Acad Sci U S A 1985; 82:6250–4.
Gough NM, Metcalf D, Gough J, Grail D, Dunn AR . Structure and expression of the mRNA for murine granulocyte-macrophage colony stimulating factor. EMBO J 1985; 4:645–53.
Farrar WL, Harel-Bellan A, Ferris DK . Biochemical and molecular events controlled by lymphokine growth factors. Soc Gen Physiol Ser 1988; 43:371–80.
Griffin JD, Cannistra SA, Sullivan R, Demetri GD, Ernst TJ, Kanakura Y . The biology of GM-CSF: regulation of production and interaction with its receptor. Int J Cell Cloning 1990; 8 Suppl 1:35–44; discussion 44–5.
Cousins DJ, Staynov DZ, Lee TH . Regulation of interleukin-5 and granulocyte-macrophage colony-stimulating factor expression. Am J Respir Crit Care Med 1994; 150:S50–3.
Nimer SD, Uchida H . Regulation of granulocyte-macrophage colony-stimulating factor and interleukin 3 expression. Stem Cells 1995; 13:324–35.
Farrar WL, Brini AT, Harel-Bellan A, Korner M, Ferris DK . Hematopoietic growth-factor signal transduction and regulation of gene expression. Immunol Ser 1990; 49:379–410.
Griffin JD, Spertini O, Ernst TJ, et al. Granulocyte-macrophage colony-stimulating factor and other cytokines regulate surface expression of the leukocyte adhesion molecule-1 on human neutrophils, monocytes, and their precursors. J Immunol 1990; 145:576–84.
Miyajima A . Molecular structure of the IL-3, GM-CSF and IL-5 receptors. Int J Cell Cloning 1992; 10:126–34.
Onetto-Pothier N, Aumont N, Haman A, et al. Characterization of granulocyte-macrophage colony-stimulating factor receptor on the blast cells of acute myeloblastic leukemia. Blood 1990; 75:59–66.
Elliott MJ, Vadas MA, Eglinton JM, et al. Recombinant human interleukin-3 and granulocyte-macrophage colony-stimulating factor show common biological effects and binding characteristics on human monocytes. Blood 1989; 74:2349–59.
Dijkers PF, van Dijk TB, de Groot RP, et al. Regulation and function of protein kinase B and MAP kinase activation by the IL-5/GM-CSF/IL-3 receptor. Oncogene 1999; 18:3334–42.
Jenkins BJ, Blake TJ, Gonda TJ . Saturation mutagenesis of the beta subunit of the human granulocyte-macrophage colony-stimulating factor receptor shows clustering of constitutive mutations, activation of ERK MAP kinase and STAT pathways, and differential beta subunit tyrosine phosphorylation. Blood 1998; 92:1989–2002.
Hanazono Y, Chiba S, Sasaki K, et al. Erythropoietin induces tyrosine phosphorylation and kinase activity of the c-fps/fes proto-oncogene product in human erythropoietin-responsive cells. Blood 1993; 81:3193–6.
Hanazono Y, Chiba S, Sasaki K, et al. c-fps/fes protein-tyrosine kinase is implicated in a signaling pathway triggered by granulocyte-macrophage colony-stimulating factor and interleukin-3. EMBO J 1993; 12:1641–6.
Goletti D, Kinter AL, Hardy EC, Poli G, Fauci AS . Modulation of endogenous IL-1 beta and IL-1 receptor antagonist results in opposing effects on HIV expression in chronically infected monocytic cells. J Immunol 1996; 156:3501–8.
Briend E, Colle JH, Fontan E, Saklani-Jusforgues H, Fauve RM . Human glycoprotein HGP92 induces cytokine synthesis in mouse mononuclear phagocytes. Int Immunol 1995; 7:1753–61.
Schwager I, Jungi TW . Effect of human recombinant cytokines on the induction of macrophage procoagulant activity. Blood 1994; 83:152–60.
Huleihel M, Douvdevani A, Segal S, Apte RN . Different regulatory levels are involved in the generation of hemopoietic cytokines (CSFs and IL-6) in fibroblasts stimulated by inflammatory products. Cytokine 1993; 5:47–56.
Megyeri P, Sadowska J, Issekutz TB, Issekutz AC . Endotoxin-stimulated human macrophages produce a factor that induces polymorphonuclear leucocyte infiltration and is distinct from interleukin-1, tumour necrosis factor alpha and chemotactic factors. Immunology 1990; 69:155–61.
Cleveland DW, Yen TJ . Multiple determinants of eukaryotic mRNA stability. New Biol 1989; 1:121–6.
Alvaro-Gracia JM, Zvaifler NJ, Brown CB, Kaushansky K, Firestein GS . Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-alpha. J Immunol 1991; 146:3365–71.
Ernst TJ, Ritchie AR, O'Rourke R, Griffin JD . Colony-stimulating factor gene expression in human acute myeloblastic leukemia cells is posttranscriptionally regulated. Leukemia 1989; 3:620–5.
Ernst TJ, Ritchie AR, Demetri GD, Griffin JD . Regulation of granulocyte- and monocyte-colony stimulating factor mRNA levels in human blood monocytes is mediated primarily at a post-transcriptional level. J Biol Chem 1989; 264:5700–3.
van Leeuwen BH, Martinson ME, Webb GC, Young IG . Molecular organization of the cytokine gene cluster, involving the human IL-3, IL-4, IL-5, and GM-CSF genes, on human chromosome 5. Blood 1989; 73:1142–8.
Shang C, Attema J, Cakouros D, Cockerill PN, Shannon MF . Nuclear factor of activated T cells contributes to the function of the CD28 response region of the granulocyte macrophage-colony stimulating factor promoter. Int Immunol 1999; 11:1945–56.
Hohaus S, Petrovick MS, Voso MT, et al. PU.1 (Spi-1) and C/EBP alpha regulate expression of the granulocyte-macrophage colony-stimulating factor receptor alpha gene. Mol Cell Biol 1995; 15:5830–45.
Suen Y, Lee SM, Schreurs J, Knoppel E, Cairo MS . Decreased macrophage colony-stimulating factor mRNA expression from activated cord versus adult mononuclear cells: altered posttranscriptional stability. Blood 1994; 84:4269–77.
Hachiya M, Suzuki G, Koeffler HP, Akashi M . Irradiation increases expression of GM-CSF in human fibroblasts by transcriptional and post-transcriptional regulation. Exp Cell Res 1994; 214:343–50.
Migliaccio AR, Jiang Y, Migliaccio G, et al. Transcriptional and posttranscriptional regulation of the expression of the erythropoietin receptor gene in human erythropoietin-responsive cell lines. Blood 1993; 82:3760–9.
Koeffler HP, Gasson J, Tobler A . Transcriptional and posttranscriptional modulation of myeloid colony-stimulating factor expression by tumor necrosis factor and other agents. Mol Cell Biol 1988; 8:3432–8.
Sagawa K, Mochizuki M, Sugita S, et al. Suppression by IL-10 and IL-4 of cytokine production induced by two-way autologous mixed lymphocyte reaction. Cytokine 1996; 8:501–6.
Ozawa H, Aiba S, Nakagawa, Tagami H . Interferon-gamma and interleukin-10 inhibit antigen presentation by Langerhans cells for T helper type 1 cells by suppressing their CD80 (B7-1) expression. Eur J Immunol 1996; 26:648–52.
Jansen JH, Wientjens GJ, Fibbe WE, Willemze R, Kluin-Nelemans HC . Inhibition of human macrophage colony formation by interleukin 4. J Exp Med 1989; 170:577–82.
Akashi K, Shibuya T, Harada M, et al. Interleukin 4 suppresses the spontaneous growth of chronic myelomonocytic leukemia cells. J Clin Invest 1991; 88:223–30.
Tsuboi A, Masuda ES, Naito Y, et al. Calcineurin potentiates activation of the granulocyte-macrophage colony-stimulating factor gene in T cells: involvement of the conserved lymphokine element 0. Mol Biol Cell 1994; 5:119–28.
Hatfield SM, Roehm NW . Cyclosporine and FK506 inhibition of murine mast cell cytokine production. J Pharmacol Exp Ther 1992; 260:680–8.
Adcock IM, Caramori G . Cross-talk between pro-inflammatory transcription factors and glucocorticoids. Immunol Cell Biol 2001; 79:376–84.
Yoshikawa H, Tasaka K . Suppression of mast cell activation by glucocorticoid. Arch Immunol Ther Exp (Warsz) 2000; 48:487–95.
Jaffuel D, Mathieu M, Godard P, Michel FB, Demoly P . Mechanism of action of glucocorticoids in asthma. Rev Mal Respir 1999; 16:431–42.
Brattsand R, Linden M . Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. Aliment Pharmacol Ther 1996; 10 Suppl 2:81–90; discussion 91–2.
Metcalf D, Nicola NA, Mifsud S, Di Rago L . Receptor clearance obscures the magnitude of granulocyte-macrophage colony-stimulating factor responses in mice to endotoxin or local infections. Blood 1999; 93:1579–85.
Drexler HG, Meyer C, Quentmeier H . Effects of FLT3 ligand on proliferation and survival of myeloid leukemia cells. Leuk Lymphoma 1999; 33:83–91.
Shannon MF, Himes SR, Coles LS . GM-CSF and IL-2 share common control mechanisms in response to costimulatory signals in T cells. J Leukoc Biol 1995; 57:767–73.
Oster W, Mertelsmann R, Herrmann F . Role of colony-stimulating factors in the biology of acute myelogenous leukemia. Int J Cell Cloning 1989; 7:13–29.
Bailer RT, Lazo A, Ng-Bautista CL, et al. Comparison of constitutive cytokine release in high and low histologic grade AIDS-related Kaposi's sarcoma cell strains and in sera from HIV+/KS+ and HIV+/KS- patients. J Interferon Cytokine Res 1995; 15:473–83.
Hamilton JA, Anderson GP . GM-CSF Biology. Growth Factors 2004; 22:225–31.
Lang RA, Metcalf D, Cuthbertson RA, et al. Transgenic mice expressing a hemopoietic growth factor gene (GM-CSF) develop accumulations of macrophages, blindness, and a fatal syndrome of tissue damage. Cell 1987; 51:675–86.
Alderuccio F, Biondo M, Toh BH . Organ-specific autoimmunity in granulocyte macrophage-colony stimulating factor (GM-CSF) deficient mice. Autoimmunity 2002; 35:67–73.
Biondo M, Nasa Z, Marshall A, Toh BH, Alderuccio F . Local transgenic expression of granulocyte macrophage-colony stimulating factor initiates autoimmunity. J Immunol 2001; 166:2090–9.
Johnson GR, Gonda TJ, Metcalf D, Hariharan IK, Cory S . A lethal myeloproliferative syndrome in mice transplanted with bone marrow cells infected with a retrovirus expressing granulocyte-macrophage colony stimulating factor. EMBO J 1989; 8:441–8.
Worgall S, Singh R, Leopold PL, et al. Selective expansion of alveolar macrophages in vivo by adenovirus-mediated transfer of the murine granulocyte-macrophage colony-stimulating factor cDNA. Blood 1999; 93:655–66.
Xing Z, Ohkawara Y, Jordana M, Graham F, Gauldie J . Transfer of granulocyte-macrophage colony-stimulating factor gene to rat lung induces eosinophilia, monocytosis, and fibrotic reactions. J Clin Invest 1996; 97:1102–10.
Xing Z, Braciak T, Ohkawara Y, et al. Gene transfer for cytokine functional studies in the lung: the multifunctional role of GM-CSF in pulmonary inflammation. J Leukoc Biol 1996; 59:481–8.
Frandji P, Tkaczyk C, Oskeritzian C, et al. Presentation of soluble antigens by mast cells: upregulation by interleukin-4 and granulocyte/macrophage colony-stimulating factor and downregulation by interferon-gamma. Cell Immunol 1995; 163:37–46.
Ohtoshi T, Takizawa H, Okazaki H, et al. Diesel exhaust particles stimulate human airway epithelial cells to produce cytokines relevant to airway inflammation in vitro. J Allergy Clin Immunol, 1998; 101:778–85.
Delneste Y, Charbonnier P, Herbault N, et al Interferon-gamma switches monocyte differentiation from dendritic cells to macrophages. Blood 2003; 101:143–50.
de Vries EG, Biesma B, Willemse PH, et al. A double-blind placebo-controlled study with granulocyte-macrophage colony-stimulating factor during chemotherapy for ovarian carcinoma. Cancer Res 1991; 51:116–22.
Stanley E, Lieschke GJ, Grail D, et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci U S A 1994; 91:5592–6.
Wada H, Noguchi Y, Marino MW, Dunn AR, Old LJ . T cell functions in granulocyte/macrophage colony-stimulating factor deficient mice. Proc Natl Acad Sci U S A 1997; 94:12557–61.
Deepe GS Jr ., Gibbons R, Woodward E . Neutralization of endogenous granulocyte-macrophage colony-stimulating factor subverts the protective immune response to Histoplasma capsulatum. J Immunol 1999; 163:4985–93.
Hamilton JA, Stanley ER, Burgess AW, Shadduck RK . Stimulation of macrophage plasminogen activator activity by colony-stimulating factors. J Cell Physiol 1980; 103:435–45.
Campbell IK, Rich MJ, Bischof RJ, Dunn AR, Grail D, Hamilton JA . Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice. J Immunol, 1998; 161:3639–44.
Hamilton JA . GM-CSF in inflammation and autoimmunity. Trends Immunol 2002; 23:403–8.
Ohta K, Yamashita N, Tajima M, et al. Diesel exhaust particulate induces airway hyperresponsiveness in a murine model: essential role of GM-CSF. J Allergy Clin Immunol 1999; 104:1024–30.
Yamashita N, Tashimo H, Ishida H, et al. Attenuation of airway hyperresponsiveness in a murine asthma model by neutralization of granulocyte-macrophage colony-stimulating factor (GM-CSF). Cell Immunol 2002; 219:92–7.
Levitt LJ, Nagler A, Lee F, et al. Production of granulocyte/macrophage-colony-stimulating factor by human natural killer cells. Modulation by the p75 subunit of the interleukin 2 receptor and by the CD2 receptor. J Clin Invest 1991; 88:67–75.
Quill H, Gaur A, Phipps RP . Prostaglandin E2-dependent induction of granulocyte-macrophage colony-stimulating factor secretion by cloned murine helper T cells. J Immunol 1989; 142:813–8.
Himes SR, Reeves R, Attema J, et al. The role of high-mobility group I(Y) proteins in expression of IL-2 and T cell proliferation. J Immunol 2000; 164:3157–68.
Ji Q, Gondek D, Hurwitz AA . Provision of granulocyte-macrophage colony-stimulating factor converts an autoimmune response to a self-antigen into an antitumor response. J Immunol 2005; 175:1456–63.
Gangi E, Vasu C, Cheatem D, Prabhakar BS . IL-10-producing CD4+CD25+ regulatory T cells play a critical role in granulocyte-macrophage colony-stimulating factor-induced suppression of experimental autoimmune thyroiditis. J Immunol 2005; 174:7006–13.
Gonzalez-Juarrero M, Hattle JM, Izzo A, et al. Disruption of granulocyte macrophage-colony stimulating factor production in the lungs severely affects the ability of mice to control Mycobacterium tuberculosis infection. J Leukoc Biol 2005; 77:914–22.
Stampfli MR, Wiley RE, Neigh GS, et al. GM-CSF transgene expression in the airway allows aerosolized ovalbumin to induce allergic sensitization in mice. J Clin Invest 1998; 102:1704–14.
Barouch DH, Santra S, Tenner-Racz K, et al. Potent CD4+ T cell responses elicited by a bicistronic HIV-1 DNA vaccine expressing gp120 and GM-CSF. J Immunol 2002; 168:562–8.
Fensterle J, Grode L, Hess J, Kaufmann SH . Effective DNA vaccination against listeriosis by prime/boost inoculation with the gene gun. J Immunol 1999; 163:4510–8.
Kim JJ, Ayyavoo V, Bagarazzi ML, et al. In vivo engineering of a cellular immune response by coadministration of IL-12 expression vector with a DNA immunogen. J Immunol 1997; 158:816–26.
Mach N, Dranoff G . Cytokine-secreting tumor cell vaccines. Curr Opin Immunol 2000; 12:571–5.
Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A 1993; 90:3539–43.
Mach N, Gillessen S, Wilson SB, et al. Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony-stimulating factor or Flt3-ligand. Cancer Res 2000; 60:3239–46.
Nieuwenhuis EE, Gillessen S, Scheper RJ, et al. CD1d and CD1d-restricted iNKT-cells play a pivotal role in contact hypersensitivity. Exp Dermatol 2005; 14:250–8.
Gillessen S, Naumov YN, Nieuwenhuis EE, et al. CD1d-restricted T cells regulate dendritic cell function and antitumor immunity in a granulocyte-macrophage colony-stimulating factor-dependent fashion. Proc Natl Acad Sci U S A 2003; 100:8874–9.
Hanahan D, Weinberg RA . The hallmarks of cancer. Cell 2000; 100:57–70.
Tao MH, Levy R . Idiotype/granulocyte-macrophage colony-stimulating factor fusion protein as a vaccine for B-cell lymphoma. Nature 1993; 362:755–8.
This work was supported in part by USPHS grants (AI43384 and AI50222), and the National Space Biomedical Research Institute (IIH00208), which is supported by the National Aeronautics and Space Administration (NASA) through the Cooperative Agreement NCC 9-58. The authors are grateful to Dr Sidney Pestka for his critical review of this manuscript.
About this article
Cite this article
Shi, Y., Liu, C., Roberts, A. et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know. Cell Res 16, 126–133 (2006). https://doi.org/10.1038/sj.cr.7310017
- granulocyte-macrophage colony-stimulating factor
- antigen presenting cells
- T cells
Effects of Pinus massoniana pollen polysaccharides on intestinal microenvironment and colitis in mice
Food & Function (2021)
Mimicking Behçet’s disease: GM‐CSF gain of function mutation in a family suffering from a Behçet’s disease‐like disorder marked by extreme pathergy
Clinical & Experimental Immunology (2021)
Inflammatory Pre-Conditioning of Adipose-Derived Stem Cells with Cerebrospinal Fluid from Traumatic Brain Injury Patients Alters the Immunomodulatory Potential of ADSC Secretomes
Journal of Neurotrauma (2021)
The increasing hematopoietic effect of the combined treatment of Korean Red ginseng and Colla corii asini on cyclophosphamide-induced immunosuppression in mice
Journal of Ginseng Research (2021)