Immune activation & hematopoiesis
Project leader: Martijn Nolte PhD
This research line focuses on the cellular and molecular mechanisms by which the activated immune system can modulate the intricate process of hematopoiesis in the bone marrow. Using both in vitro and in vivo models, we focus on the molecular mechanism by which several types of immune cells are able to influence the function of stem and progenitor cells. With the approach chosen for this line of research, we operate at the crossroads of hematology and immunology. These two disciplines clearly have a direct affiliation, but are infrequently combined in fundamental research. With this approach, we aim to give insight in a, so far, unexplored aspect of hematopoietic regulation, which will contribute to a better understanding of the consequences of immune activation.
With the aim of investigating the impact of immune activation on hematopoiesis we have found that activated T cells in the bone marrow (BM) are able to provide feedback signals during the course of a viral infection. We found that activated T cells in the BM can inhibit the production of both eosinophilic (De Bruin et al., Blood 2010) and neutrophilic granulocytes (De Bruin et al., Blood 2012) through the production of the pro-inflammatory cytokine interferon-gamma (IFNγ). Molecular analysis revealed that IFNγ-treatment of myeloid precursors negatively affects the signaling pathways downstream of the IL-5R and the G-CSFR, which are essential for the formation of eosinophilic and neutrophilic granulocytes, respectively. Conversely, IFNγ rather enhanced the production of monocytes by upregulating the monocyte-inducing transcription factors IRF-8 and PU.1 (De Bruin et al., Blood 2012). These findings illustrate that IFNγ-producing T cells are important mediators in shaping the hematopoietic response during inflammation, as they promote the production of the appropriate myeloid cell type upon viral infection and simultaneously suppress formation of cells that are less important for anti-viral defense.
Apart from the impact of IFNγ on hematopoiesis in the short term, we found that sustained production of IFNγ induces a progressive form of anemia, which could be attributed to a reduction in the lifespan as well as the formation of red blood cells. The decrease in erythrocyte half-life could be explained by an IFNγ-induced activation of macrophages in the splenic red pulp (Libregts et al., Blood 2011). We have demonstrated that IFNγ induces expression of the transcription factor IRF-1, which subsequently binds to the promoter of PU.1 and induces PU.1 expression, leading to inhibition of erythropoiesis. Notably, down regulation of either IRF-1 or PU.1 expression was sufficient to overcome IFNγ-induced inhibition of erythropoiesis (Libregts et al., Blood 2011). The findings described above illustrate how T cells in the BM can have a strong impact on the formation of new blood cells in the BM, through the production of IFNγ (Figure 2). Although a temporary shift in hematopoiesis might be beneficial during acute viral infections, the prolongation of such a shift can lead to the development of anemia, which is frequently observed in patients suffering from chronic inflammatory diseases, such as HIV-infection and rheumatoid arthritis. Moreover, a prolonged blockade in the formation of eosinophilic and neutrophilic granulocytes will also impair anti-bacterial responses, which could explain the increased vulnerability to bacterial infections that occurs after a viral infection.
Figure 2: Our data demonstrate that IFNγ produced by activated T cells can dramatically alter the hematopoietic differentiation in the bone marrow. IFNγ was shown to negatively affect differentiation towards both eosinophilic and neutrophilic granulocytes, as well as red blood cells (red dotted arrows), whereas it strongly enhances the formation of monocytes (large red arrow).
- Koning JJ, Kooij G, de Vries HE, Nolte MA, Mebius RE. Mesenchymal stem cells are mobilized from the bone marrow during inflammation. Front Immunol. 2013;4:49.
- De Bruin AM, Libregts SF, Valkhof M, Boon L, Touw IP, Nolte MA. Interferon-gamma induces monopoiesis and inhibits neutrophil development during inflammation. Blood 2012; 119(6):1543-54.
- Libregts SF, Gutiérrez L, de Bruin AM, Wensveen FM, Papadopoulos P, van IJcken W, Özgür Z, Philipsen S and Nolte MA. Chronic IFNγ production in mice induces anemia by reducing erythrocyte lifespan and inhibiting erythropoiesis through an IRF-1/PU.1-axis. Blood 2011; 118(9):2578-88.
- De Bruin AM, Buitenhuis M, van der Sluijs KF, van Gisbergen KP, Boon L, Nolte MA. Eosinophil differentiation in the bone marrow is inhibited by T cell-derived IFN-gamma. Blood 2010; 116(14):2559-69.
- Nolte MA, van Olffen RW, van Gisbergen KP, van Lier RA. Timing and tuning of CD27-CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology. Immunol Rev 2009; 229(1):216-31. Review.
- Nolte MA, Arens R, van Os R, van Oosterwijk M, Hooibrink B, van Lier RA, van Oers MH. Immune activation modulates hematopoiesis through interactions between CD27 and CD70. Nat Immunol 2005; 6(4):412-8.