Download Back to the roots: Networking T cells in the bone marrow

Back to the roots: Networking T cells in the bone marrow
Martijn Nolte, Sanquin, Amsterdam, The Netherlands. ([email protected])
Bone marrow is a highly dynamic organ, in which cellular networking is essential to ensure the
continuous release of new blood cells, which has been estimated at a staggering rate of ~5 million
cells per second! The hematopoietic process responsible for this huge production is tightly controlled,
as too few or too many blood cells is obviously detrimental to human health and will have clinical
consequences. A balanced level of differentiation of hematopoietic stem or progenitor cells to mature
blood cells is already an intricate process during the steady state, but it becomes even more complex
upon infection. When we are under attack from a pathogen, the bone marrow receives cues to
enhance the production of the appropriate type of blood cell to combat the infection, whereas the
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generation of other cell types is temporarily inhibited . Although it has been recognized that such a
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tailored response from the bone marrow occurs during an infection , the underlying cellular and
molecular mechanisms are not yet fully understood. In recent years, we have analyzed the presence
and function of T cells inside the bone marrow and in this lecture I will show that these immune cells
are important regulators of hematopoiesis.
Apart from being the major hematopoietic organ, bone marrow also acts as a genuine secondary
lymphoid organ, as it enables the activation of naïve T cells by local dendritic cells. Furthermore,
memory T cells are known to refuel in the bone marrow, as they receive key survival signals through
IL-7 and IL-15 from local stromal cells. The role of the bone marrow as a memory organ should not be
underestimated, as we found after a viral infection in mice that the vast majority of virus-specific
memory CD8 T cells is not located in spleen or lymph nodes, but inside the bone marrow, particularly
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in the vertebrae . The ability for T cells to migrate to and through the bone marrow also enables them
to modulate the hematopoietic process. We found that the production of IFN- by activated T cells is
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sufficient to enhance the formation of monocytes , but it inhibits the development of most other blood
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cell lineages , as well as the self-renewal of hematopoietic stem cells (HSCs) . Importantly, T cells
can also influence the hematopoietic process without being activated: using several mouse models,
we found that the number of memory T cells in bone marrow positively correlates with the number of
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HSCs. We could demonstrate that memory CD8 T cells actually enhance the self-renewal capacity of
HSCs in vitro and in vivo, without impairing their ability to differentiate. This effect could be attributed
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to the production of soluble factor(s) by memory CD8 T cells, both in steady state and following acute
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or chronic viral infection. These findings provide evidence that memory CD8 T cells not only go back
to their bone marrow roots to receive survival cues, but also use their communication skills to support
the function of HSCs in the steady state and skew hematopoietic differentiation when they get
activated (see Figure). These findings add a whole new functional perspective to T cell biology, which
is also clinically relevant: our findings can explain why chronic infections frequently lead to the
development of anemia and why memory CD8 T cells enhance HSC engraftment upon
transplantation. Increasing our understanding of this immune-hematopoietic network and the
molecular crosstalk between immune cells and hematopoietic progenitor cells is therefore of great
importance.
Selected references from my group for further reading:
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Maria F. Pascutti, Martje N. Erkelens, Martijn A. Nolte (2016). Impact of Viral Infections on Hematopoiesis:
From Beneficial to Detrimental Effects on Bone Marrow Output. Front Immunol. 7:364.
Sten F. Libregts and Martijn A. Nolte (2014). Parallels between immune driven-hematopoiesis and T-cell
activation: 3 signals that relay inflammatory stress to the bone marrow. Experimental Cell Research,
329(2):239-47.
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Sulima Geerman, Sarah Hickson, Giso Brasser, Maria Fernanda Pascutti, Martijn A. Nolte (2016).
Quantitative and Qualitative Analysis of Bone Marrow CD8(+) T Cells from Different Bones Uncovers a Major
Contribution of the Bone Marrow in the Vertebrae. Front Immunol., 6:660.
Interferon-gamma induces monopoiesis and inhibits neutrophil development during inflammation. Blood,
119(6):1543-1554.
Sten F. Libregts, Laura Gutiérrez, Alexander M. de Bruin, Felix M. Wensveen, Petros Papadopoulos, Wilfred
van IJcken, Zeliha Özgür, Sjaak Philipsen and Martijn A. Nolte (2011). Chronic IFN production in mice
induces anemia by reducing erythrocyte lifespan and inhibiting erythropoiesis through an IRF-1/PU.1-axis.
Blood, 118(9):2578-2588.
Alex M. de Bruin, Miranda Buitenhuis, Koen F. van der Sluijs, Klaas P.J.M. van Gisbergen, Louis Boon,
Martijn A. Nolte (2010). Eosinophil differentiation in the bone marrow is inhibited by T cell-derived IFN
Blood, 116(14):2559-2569.
Alexander M. de Bruin, Özlem Demirel, Berend Hooibrink, Christian H. Brandts, and Martijn A. Nolte (2013).
Interferon- impairs proliferation of hematopoietic stem cells in mice. Blood, 121(18):3578-3585.
Alexander M. de Bruin, Carlijn Voermans, Martijn A. Nolte (2014). Impact of interferon-γ on hematopoiesis.
Blood, 124(16):2479-86.