A study by Wanqiang Sheng and colleagues from the National University of Singapore, published in Cell Research identifies a new subset of T helper (Th) cells that may play a key role in autoimmune neuroinflammatory conditions such as multiple sclerosis.
Recent evidence indicates that granulocyte-macrophage colony-stimulating factor (GM-CSF) is a major encephalitogenic factor contributing to neuroinflammation and experimental autoimmune encephalomyelitis, the animal model of human demyelinating diseases, including multiple sclerosis (L.Codarri et al., Nature Immunology 2011, 12:560; M. El-Behi et al., Nature Immunology 2011, 12:568). A new study also suggests a pathogenic role for GM-CSF+ T cells in the inflamed brain of multiple sclerosis patients (R.Noster et al., Sci Transl Med, 2014, 241:241ra80).
Now, the research group from Singapore found that interleukin (IL)-7, signaling through STAT5, induces the development of a Th subset of cells (Th-GM) that predominantly produce GM-CSF and IL-3.
According to the authors (and cf. recent work indicating that anti-IL-23 receptor antibodies failed in treating multiple sclerosis), the function of IL-23 in multiple sclerosis is most likely compensated by other factors. Thus, in their study they found that Th-GM cells produced greater amounts of GM-CSF than Th1 or Th17 cells, suggesting that Th-GM cells are the major source of GM-CSF in T cell-mediated neuronal inflammation. This subset of Th cells was essential for the pathogenesis of experimental autoimmune encephalomyelitis, but not in experimental colitis.
The authors suggest that GM-CSF-producing CD4+ T cells regulated by IL-7-STAT5 signaling axis represent a new Th subset with a distinct differentiation program and cytokine production profile.
A 2015 review by Andrew Croxford, Sabine Spath and Burkhard Becher highlights the role of GM-CSF in neuroinflammation, indicating that GM-CSF produced by Th cells coordinates monocyte recruitment to the central nervous system, and differentiation into pathogenic effectors.
According to this review GM-CSF expression by autoreactive Th cells is crucial for their pathogenic potential and the activation of inflammatory phagocytes. Also, GM-CSF initiates inflammatory gene expression in monocytes and their progeny during an autoimmune episode. And, differentiated, inflammatory monocytes are highly abundant in inflamed tissue and represent major executers of GM-CSF-dependent pathogenesis.
A 2019 review by Francesco Borriello et al. highlights the importance of GM-CSF and IL-3 as new established critical modulators of the innate immune response by acting directly on mature immune cells. Of note, this new role of these cytokines has been implicated in the pathogenesis of a range of diseases and are now been investigated as immunostimulating agents in cancer therapy.
Of particular interest, it is now known that GM-CSF and to a lesser extent IL-3 play a critical role in experimental models of trained immunity by acting not only on bone marrow precursors but also directly on mature myeloid cells.
Some highlights from this overview.
GM-CSF and IL-3 in Sepsis
It appears that GM-CSF and IL-3 play a central role in the pathogenesis of sepsis and might also be exploited for diagnostic or therapeutic purposes.
In murine models of sepsis GM-CSF increases survival, and, thus, GM-CSF has also been tested as an immunostimulating adjuvant therapy. But clinical results have been inconclusive so far. Recent evidence indicates that increased IL-3 plasma levels are associated with high organ failure rates and holds promises for implementing the use of IL-3 as a biomarker of sepsis in the clinical setting.
GM-CSF and IL-3 in autoimmune and allergic Diseases
New evidence indicates a prominent role for GM-CSF and to a lesser extent IL-3 in autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). It appears that GM-CSF acts on monocytes to promote the expression of a pathogenic program characterized by genes linked to inflammasome function, phagocytosis and chemotaxis. GM-CSF is currently under investigation as a therapeutic target in patients with MS and a phase Ib clinical trial using a recombinant human anti-GM-CSF antibody.
IL-3 plays a central role in modulating basophil and mast cell expansion and activity in the context of type 2 (allergic) responses. Th2 lymphocytes secrete IL-3 that expand and recruit basophils, which in turn reinforce Th2 polarization.
GM-CSF and IL-3 in cardiovascular diseases
Several lines of evidence support the notion that GM-CSF exerts a pro-atherogenic role. GM-CSF production by cardiac fibroblast has also been implicated in the pathogenesis of Kawasaki disease (KD). This is a systemic vasculitis of the childhood that particularly affects coronary arteries and therefore represents a leading cause of pediatric heart disease in developed countries.
Also, it is known that Group A streptococcus (GAS) infection is related to delayed autoimmune response in acute rheumatic fever (ARF), which often involves the heart. Interestingly, peripheral blood mononuclear cells isolated from ARF patients and stimulated in vitro with GAS produce more CD4+ T cell-derived GM-CSF compared to healthy controls.
GM-CSF and IL-3 in cancer therapy
It is becoming clear that GM-CSF is highly expressed in the milieu of several cancers and has been variably associated with pro- or anti-tumorigenic functions. Combining GM-CSF to the anti-CTLA-4-blocking antibody Ipilimimab increases the efficacy of the latter in patients with metastatic melanoma. IL-3 or its specific receptor subunit CD123 has been investigated as therapeutic targets, especially in acute myeloid leukemia (AML), where CD123 expression on cancer cells correlates with reduced patient survival.