License to subdue
It has long been a puzzle how monocytes can execute entirely opposing immunological programs by either fostering or suppressing inflammation. This puzzle has now been solved in a collaboration project with the group of Prof. Manfred Lutz at the Institute of Immunobiology at Würzburg University.
In a new publication by Eliana Ribechini et al. we show that effector functions of differentiating monocytes all depend on the right timing: Early in an immune response, when monocytes encounter activated T cells producing the important cytokines GM-CSF and IFN-γ at inflammatory sites, they differentiate into activated macrophages or dendritic cells and enhance the immune response. However, later in an immune response, monocytes within the bone marrow or spleen are exposed to systemically elevated GM-CSF cytokine levels before they encounter IFN-γ-producing T cells. This means that a two-step licensing process takes place that monocytes can turn into immunosuppressive cells, which are also termed myeloid-derived suppressor cells.
From a theoretical point of view, this seminal work by Ribechini et al. explains the often-contradicting reports about the role of GM-CSF in inflammation and demonstrates that there are not precommitted monocyte precursor cells in the body that either differentiate into pro- or into anti-inflammatory cells. Instead, the results clearly point to a model of suppressor monocyte activity that involves an essential time delay in their development.
These findings have important clinical implications as time-dependent monocyte licensing strikes the balance of immunogenic and suppressive effects of GM-CSF treatment in vivo. These findings also explain why immediate low dose GM-CSF treatment can help to control lethal acute infections, e.g. acute candidiasis sepsis. In this case, GM-CSF treatment will support monocyte differentiation to protect from infections. However, in another scenario, e.g. when proinflammatory cytokines together with GM-CSF are abundant, such as in a chronic inflammatory process or in cancer, monocytes will be rendered immunosuppressive and can hamper the efficient immunological control of malignant diseases.
Conclusively, novel GM-CSF signaling pathways through IFN-γR/IRF-1 and AKT/mTOR provide monocyte licensing for suppressor function in a timed two-step process. Only licensed but not fresh human CD14+ or mouse Ly-6Chigh monocytes secrete the immunosuppressive mediators IDO or nitric oxide for effector T lymphocyte suppression.
This paper by Eliana Ribbecchini et al. has now been published in the new journal Blood Advances. The research team under the guidance of Prof. Manfred Lutz included scientists from the Universities of Würzburg, Regensburg, Erlangen and Marburg.
Reference: Ribechini E, Hutchinson JA, Hergovits S, Heuer M, Lucas J, Schleicher U, Jordán Garrote AL, Potter SJ, Riquelme P, Brackmann H, Müller N, Raifer H, Berberich I, Huber M, Beilhack A, Lohoff M, Bogdan C, Eyrich M, Hermanns H, Geissler EK, Lutz MB. (2017). Novel GM-CSF signals via IFNgR/IRF-1 and AKT/mTOR license monocytes. Blood Advances 1:947-960.