E X PE R IM ENTA L C ELL R E S EA RC H

3 29 (2014) 2 39 – 247

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/yexcr

Review Article

Parallels between immune driven-hematopoiesis and T cell activation: 3 signals that relay inflammatory stress to the bone marrow Sten F.W.M. Libregts1, Martijn A. Nolten Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands

article information

abstract

Article Chronology:

Quiescence, self-renewal, lineage commitment and differentiation of hematopoietic stem cells (HSCs)

Received 15 June 2014

towards fully mature blood cells are a complex process that involves both intrinsic and extrinsic signals.

Received in revised form

During steady-state conditions, most hematopoietic signals are provided by various resident cells inside

8 September 2014

the bone marrow (BM), which establish the HSC micro-environment. However, upon infection, the

Accepted 11 September 2014

hematopoietic process is also affected by pathogens and activated immune cells, which illustrates an

Available online 22 September 2014

effective feedback mechanism to hematopoietic stem and progenitor cells (HSPCs) via immune-

Keywords:

mediated signals. Here, we review the impact of pathogen-associated molecular patterns (PAMPs),

HSC

damage-associated molecular patterns (DAMPs), costimulatory molecules and pro-inflammatory

Hematopoiesis

cytokines on the quiescence, proliferation and differentiation of HSCs and more committed progenitors.

Immune activation TLRs

As modulation of HSPC function via these immune-mediated signals holds an interesting parallel with the “three-signal-model” described for the activation and differentiation of naïve T-cells, we propose a

Co-stimulation

novel “three-signal” concept for immune-driven hematopoiesis. In this model, the recognition of

Cytokines

PAMPs and DAMPs will activate HSCs and induce proliferation, while costimulatory molecules and proinflammatory cytokines confer a second and third signal, respectively, which further regulate expansion, lineage commitment and differentiation of HSPCs. We review the impact of inflammatory stress on hematopoiesis along these three signals and we discuss whether they act independently from each other or that concurrence of these signals is important for an adequate response of HSPCs upon infection. & 2014 Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 Parallels between differentiation of T cells and HSPCs: introducing a three-signal model. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 Signal 1: activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 n

Corresponding author. Fax: þ31 20 512 3474. E-mail address: [email protected] (M.A. Nolte). 1 Current address: Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.

http://dx.doi.org/10.1016/j.yexcr.2014.09.016 0014-4827/& 2014 Elsevier Inc. All rights reserved.

240

Signal 2: costimulation . . . . . . . . Signal 3: inflammatory cytokines Conclusions and implications . . . Acknowledgments . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .

E XP ER I ME NTAL C E LL RE S E ARCH

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

Introduction Hematopoiesis is the delicate process of development, production and specialization of blood cells in the BM. All hematopoietic lineages find their origin in one population of common progenitor cells, the hematopoietic stem cells (HSCs). HSC behavior was initially thought to be stochastic and independent of extrinsic factors, but findings from the last 2 decades revived Schofield's niche concept, and highlight the importance of the microenvironment in regulating plasticity of hematopoiesis [1,2]. Schofield described the niche for HSCs as an anatomical location that affects stem cell number and behavior by inducing self-renewal in proximity of this location or inducing differentiation at a distance [3]. The HSC niche, which comprises both hematopoietic and nonhematopoietic cells, does not only provide anatomical space for HSCs, but also supplies HSCs with signals for their maintenance, quiescence, self-renewal, proliferation and differentiation [2,4]. Besides the presence of HSC niches there are several other hematopoietic niches that harbor distinct hematopoietic progenitors with either full or restricted hematopoietic capacities [5,6]. Several types of niche cells control the maintenance and function of the hematopoietic stem and progenitor cells (HSPCs) through cell–cell interaction and/or the production of essential soluble factors, such as chemokines and growth factors [2,4]. This is the case for the steady-state situation, but it is less clear how the hematopoietic process is regulated during cellular stress situations, like anemia and inflammation, when hematopoietic output needs to be adjusted in order to cope with the body's altered needs. Adaptation of hematopoiesis during inflammation was first considered to be mainly regulated by systemic changes in hematopoietic cytokine levels, but evidence is accumulating that pathogens and activated immune cells can also directly influence HSPCs inside the BM [7,8]. Immune-mediated feedback signals can thereby quickly adjust the output of hematopoietic progenitors to generate specific offspring required for fighting the invading pathogen or to cope with the loss of specific blood cells. It is therefore of interest that BM not only serves as the primary site for hematopoiesis, but also acts as a microenvironment where immune cells can be activated or recruited to during immune activation [9–12]. Moreover, innate and adaptive immune cells that reside in the BM are generally found in close proximity of HSPCs and largely rely on the same retention factors as HSPCs [13,14]. Here we will review how inflammatory stress signals can modify the function of HSPCs and thereby modulate BM output.

Parallels between differentiation of T cells and HSPCs: introducing a three-signal model HSPCs are not only regulated by intrinsic stimuli from the niche, but also express pathogen recognition receptors (PRRs), costimulatory receptors and pro-inflammatory cytokine receptors that allow HSPCs to respond to infection and inflammation. All three types of

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

3 29 (2 014 ) 23 9 –247

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

242 242 244 245 245

inflammatory receptors have been well characterized in guiding adaptive immune responses against an invading pathogen and it is intriguing to realize that the same molecules also enable the hematopoietic system to respond to the infection. In fact, this inflammatory parallel can even be taken one step further, as modulation of HSPC function through these pro-inflammatory molecules shows a striking analogy with the “three-signal model” described for T cell activation. In this concept, naïve T cells rely for their full effector cell formation on three distinct signals that are induced by dendritic cells (DCs) (Fig. 1) [15]. The first signal in this model is provided when the highly specific T cell receptor (TCR) interacts with its cognate antigen peptide presented by major histocompatibility complex (MHC) molecules on DCs, leading to activation of the T cell. Co-stimulatory molecules expressed by DCs provide a second signal that drives survival, proliferation and differentiation of T cells during their activation. The third signal skews the differentiation towards a particular type of effector T cell and is provided by cytokines derived from the activated DC [15]. We realized that hematopoietic lineage commitment during immune activation has a striking analogy with these three steps involved in T cell activation, as differentiation of quiescent HSCs first requires activation, while costimulatory molecules and inflammatory cytokines further drive the lineage commitment and differentiation (Fig. 1). We here explore immune-driven hematopoiesis along this three-signal model and discuss the inflammatory signals that, independently or in synergy with each other, are capable of regulating HSPC proliferation, lineage commitment and differentiation

Signal 1: activation T cells are able to recognize an invading pathogen when their unique TCR interacts with a cognate peptide–MHC complex presented by DCs, which elicits Signal 1 and induces T cell activation [15]. HSPCs obviously do not express TCRs, but they are able to respond to an infection and become activated upon recognition of pathogenassociated molecular patterns (PAMPs) through expression of PRRs. HSPCs express Toll-like receptor (TLR) 2, 3, 4, 7 and 9 (reviewed in [8]), which allows them to respond to various bacterial products. Injection of mice with LPS, a TLR4-ligand, activates quiescent HSCs and turns them into self-renewing and proliferating HSCs. Whereas lineage restriction is not altered in LPS-stimulated HSCs, it does impair their repopulation capacity [16,17]. Furthermore, triggering of TLR2 and TLR4 on HSPCs induces proliferation and myeloid differentiation, whereas stimulation of granulocyte–monocyte progenitors (GMPs) drives their development towards monocytes and macrophages, and common lymphoid progenitors (CLPs) towards DCs at the expense of B-cell differentiation [18]. Interestingly, stimulation of HSPCs through TLR4 even induces the production of various proinflammatory cytokines by these cells, which is enhanced when TLR2 is also triggered [19]. The production of TLR-induced IL-6 is particularly relevant in this respect, as it induces myelopoiesis and HSPC proliferation in a paracrine manner and mediates myeloid recovery

E XP E RI ME N TAL CE L L R ES E ARC H

Resting T cell

241

32 9 (2 014 ) 2 39 – 247

T cell activation Dendritic Cell Signal 3 Cytokine Receptor

Signal 1 T Cell Receptor

Signal 2 Costimulatory Receptor

Steady-state Hematopoiesis

Immune-driven Hematopoiesis

Hematopoietic Niche Cells

Activated Immune Cell Quiescent HSC

Activated HSC Signal 2 Costimulation

Signal 1 Activation via PAMPs & DAMPs

Signal 3 Inflammatory Cytokines

Fig. 1 – Schematic overview of the 3-signal model for immune-driven hematopoiesis. Upper panel: T cells require three distinct signals that induce full activation and differentiation into a pool of effector cells. Signal 1 is ligation of the TCR with its cognate antigenic peptide presented by an MHC molecule expressed on the surface of a dendritic cell (DC). Triggering of co-stimulatory receptors on the T cell with its ligand on the DC provides a second signal, whereas DC-derived cytokines present the third signal. Lower panel: during steady-state conditions hematopoietic niche cells carefully regulate dormancy, quiescence, proliferation and differentiation of hematopoietic stem cells (HSCs) via cell–cell interactions, chemotactic signals and by the production of soluble factors. During inflammatory conditions however, pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) can activate HSCs (Signal 1). Upon activation of HSCs self-renewal, proliferation, migration and differentiation are induced and activated immune cells can then via co-stimulatory molecule signaling (Signal 2) and inflammatory cytokine signaling (Signal 3) further affect lineage commitment and differentiation of HSCs.

during neutropenia [19]. Similar to TLR2 and TLR4, TLR3 and TLR9 can also modulate hematopoiesis. Whereas stimulation of TLR3 by the double-stranded RNA mimic polyinosinic:polycytidylic acid (Poly(I:C)) induces HSC proliferation and negatively affects long-term reconstitution capacity [20–22], TLR9 signaling stimulates the differentiation of CLPs to DCs, while it inhibits the outgrowth of B-cells [23]. Signaling of human HSPCs through TLR2 and TLR7/8 was also shown to induce their differentiation towards the myeloid lineage [24,25]. This is clinically relevant, as TLR-signaling has been implicated in the pathogenesis of myelodysplastic syndromes (MDS) [26]. Next to the effect of individual PAMPs, a recent study addressed the importance of the commensal microbiota on hematopoiesis [27]. Germ-free mice

display diminished numbers of myeloid progenitors and innate immune cell populations. Although unknown which molecular factors are involved, recolonization of germ-free mice with a complex gut microbiota restored the myeloid defects, suggesting that the microbiota maintains myelopoiesis and promotes host resistance to infection with pathogens [27]. HSPCs can also be influenced by danger signals derived from damaged cells, the so-called damage-associated (or danger-associated) molecular patterns (DAMPs). Release of the chromatin protein HMGB1 from necrotic cells triggers an inflammatory response and increased HMGB1 levels sustain the inflammatory BM microenvironment in patients with chronic idiopathic

242

E XP ER I ME NTAL C E LL RE S E ARCH

neutropenia through TLR4 [28]. HSPCs can also respond to adenosine, which is also released from necrotic cells, and depending on whether the adenosine receptor 1 or 3 is triggered, this will lead to either inhibition or stimulation of HSPC proliferation, respectively (reviewed in [29]). Furthermore, the release of nucleotides from damaged or dying cells can also be sensed by purinergic receptors and it has been shown that expression of the G-protein-coupled purinergic receptor P2Y14 on HSPCs will prevent them from going into senescence upon induction of tissue stress by radiation, aging, chemotherapy, or serial BM transplantation [30]. In conclusion, HSPCs can respond directly to inflammatory danger signals, mediated by PAMPs or DAMPs (Table 1).

Signal 2: costimulation Costimulatory molecules are classically associated with the activation of lymphocytes and their modulatory actions on immune responses. It is therefore surprising that HSPCs also express various costimulatory molecules on their cell surface. CD27, which belongs to the TNF receptor superfamily, is expressed in mice on a variety of adult HSPCs, including long-term reconstituting HSCs (LT-HSC), short-term reconstituting HSCs (ST-HSCs), multipotent progenitors (MPPs), CLPs, common myeloid progenitors (CMPs) and GMPs, but not on megakaryocyte–erythroid progenitors (MEPs) [31–33] (De Bruin et al., unpublished data). CD27-deletion enhances myeloid and lymphoid differentiation of murine HSPCs, whereas triggering CD27 with its sole ligand, CD70, has the reverse effect [32]. Within the lymphoid compartment, CD27-triggering impairs the outgrowth of B cells and NK cells from the BM [32,34]. Interestingly, we found evidence that in vivo ligation of CD27 is sufficient to enhance HSC self-renewal, and leads to an accumulation of LT-HSCs and ST-HSCs in the BM (De Bruin et al., unpublished data). To what extent this is important during pro-inflammatory stress on the BM is yet unclear. Finally, CD27 expression is very low on human HSPCs, but it is upregulated on chronic myelogenous leukemia stem cells, where its signaling contributes to disease progression by activating the Wnt pathway [33]. In addition to CD27, also the TNFR superfamily members 4-1BB (CD137) and 4-1BB ligand (4-1BBL/CD137L) influence hematopoiesis [35]. Where 4-1BB is expressed on HSCs, CMPs and GMPs, 41BBL expression is found on activated myeloid progenitors. Although not extensively studied regarding their role in hematopoiesis, targeted deletion of these molecules during steady-state conditions led to conflicting results. One study suggested an inhibitory effect of 4-1BB ligation on myelopoiesis as they found a decrease of GMPs, myeloid cells and mature dendritic cells in the BM [35], while another report showed that 4-1BB induces proliferation of HSPCs and enhanced differentiation to macrophages [36]. However, it was also shown that infections with various viral and bacterial pathogens increase the number of 4-1BB expressing CD4 T-cells in BM and that 4-1BB plays an important in infection-induced myelopoiesis both in vitro and in vivo [37]. This illustrates that interactions between 4-1BB and 4-1BBL have distinct hematopoietic consequences, as they inhibit myelopoiesis during steady-state conditions, but increase myelopoiesis upon infection. CD40 and CD154 (CD40L) interactions were originally found to be critically involved in B-cell activation, T cell activation, germinal center formation and memory cell formation as they are

3 29 (2 014 ) 23 9 –247

expressed on a variety of immune cells [38]. However, CD40 expression is also found on hematopoietic progenitors. Homeostatic levels of CD154 play a critical role in the development of naive CD4þ T cells and B-cell precursors and a role for CD40– CD154 interaction has been suggested in the development of NK cells (reviewed in [39]). CD40 ligation on HSPCs results in their proliferation and induces the formation of DCs [40]. Interestingly, CD40–CD154 interactions can also modulate HSPC indirectly, as CD40 ligation on BM stromal cells increases the expression of thrombopoietin and Flt3L, thereby inducing myelopoiesis [41]. In addition, CD40 ligation on BM stromal cells during steady-state conditions induces the expression of GM-CSF, G-CSF and M-CSF, indicating a role for CD40 and CD154 in inducing myelopoiesis in general, and granulopoieis in particular [41,42]. In an inflammatory micro-environment however, when CD40 expression is further induced on granulocytic progenitor and precursor cells, CD154 rather inhibits granulopoiesis by inducing apoptosis [42]. From these studies it is thus clear that triggering of costimulatory molecules can directly modulate hematopoietic output, though the inflammatory context is important for the functional consequence (Table 1). It will be interesting to see whether other members of the TNF-receptor or even the B7/CD28 superfamily are also important in this respect. An important notion to consider when a parallel is drawn to T cells is that HSPCs can be functionally modulated by costimulatory molecules seemingly independently from Signal 1, whereas TCR-triggering is an absolute prerequisite for the activation and differentiation of naïve T cells. However, it is important to consider that the expression of most costimulatory molecules is upregulated upon infection, which may imply that Signals 1 and 2 can act in conjunction on HSPCs in the inflamed BM. The functional implication of a combination of such signals remains to be investigated.

Signal 3: inflammatory cytokines Like during T cell activation, where cytokines provide Signal 3 to induce T helper subset differentiation and differentiation into memory and effector T cells, lineage commitment of hematopoietic progenitors can also be driven by cytokines. Cytokines like GM-CSF, G-CSF, M-CSF, IL-3, IL-6 and IL-7 play an important role in the differentiation of HSPCs during steady-state hematopoiesis and their production is generally increased during immune activation (reviewed in [8,43]). In addition to these well-known hematopoietic cytokines, more and more studies show that proinflammatory cytokines produced by activated immune cells in the BM also have a major impact on HSPC function and lineage commitment. In fact, the majority of HSPCs express receptors for a plethora of pro-inflammatory cytokines [8] and we will focus here on these cytokines in the context of Signal 3. TNF-α negatively affects HSC function both in vitro and in vivo. Addition of TNF-α to in vitro colony assays significantly reduces the number of colonies generated from HSCs and affects their self-renewal and reconstitution capacity by the induction of Fas expression [44–47]. In vivo administration of TNF-α induces a strong reduction in BM cellularity and suppresses the function of actively cycling HSCs [48]. TNF receptor (TNFR) deficient mice have normal numbers of HSCs, but their long-term reconstitution in competitive repopulation assays is diminished, thereby further illustrating the inhibiting effects of TNF-α [46,48]. As there are

Table 1 – The effect of various pro-inflammatory molecules on hematopoiesis. Receptor

Effect of triggering on hematopoiesis

In vitro/ In vivo

References

1: Activation

PAM3CSK

TLR2

Enhances HSPC proliferation and myeloid differentiation.

In vitro/In vivo In vitro/In vivo In vitro/In vivo In vitro/In vivo In vitro/In vivo In vitro/In vivo In vitro/In vivo In vitro In vitro/In vivo In vitro In vitro/In vivo In vitro/In vivo In vitro/In vivo In vitro/In vivo In vitro In vitro In vitro/In vivo In vitro In vivo In vitro/In vivo In vitro/In vivo In vitro/In vivo In vitro/In vivo

[18,19,24]

Drives GMPs to monocytes and macrophages Drives CLPs to DCs at the expense of B cells Poly(I:C)

TLR3

Induces HSC proliferation and impairs reconstitution capacity

LPS

TLR4

Enhances HSPC proliferation and myeloid differentiation. Drives GMPs to monocytes and macrophages Drives CLPs to DCs at the expense of B cells

2. Costimulation

3. Inflammatory cytokines

R848 CpG DNA

TLR7/8 TLR9

Enhances HSPC differentiation to myeloid cells Drives CLPs to DCs at the expense of B cells

HMGB1 Adenosine

TLR4 A1/3AR

May sustain inflammation in BM through TLR4 signaling Regulates HSPC proliferation, dependent on the receptor.

Nucleotides

P2Y14

Inhibits stress-induced HSPC senescence

CD70

CD27

Enhances HSC self-renewal and inhibits myeloid differentiation, as well as NK and B cell development.

4-1BBL

4-1BB

Inhibits myelopoiesis during steady-state conditions, but increases myelopoiesis upon infection

CD40L

CD40

TNF-α

TNFRI/II

Enhances HSPC proliferation and enhances myelopoiesis by acting on BM stromal cells Inhibits granulopoiesis upon inflammation Inhibits the self-renewal and reconstitution capacity of HSCs

IFN-α/β IFN-γ

IFNα/βR IFNγR

Inhibits erythropoiesis Induces BM aplasia and transient HSC proliferation in vivo, though it impairs HSC reconstitution Inhibits HSC self-renewal, B cell differentiation and erythropoiesis, while enhancing myelopoiesis

IL-1

IL-1R

Within the myeloid compartment it enhances monopoiesis, while inhibiting neutrophil and eosinophil formation Induces proliferation of HSCs and myeloid progenitors and enhances granulopoiesis, mediated by stromal cells

IL-17

IL-17R

By acting on stromal cells, it induces HSPC proliferation, enhances granulopoiesis and early stage erythropoiesis, but inhibits late stage erythoid outgrowth

[20–22] [16–19]

[25] [23] [28] Reviewed in [29] [30] [31–34], De Bruin et al., unpublished [35–37] [39–42] [44–49]

32 9 (2 014 ) 2 39 – 247

Ligand

E XP E RI ME N TAL CE L L R ES E ARC H

Signal

[20,53,55] [47,53,56–59,61,64–69]

[70] [71]

243

244

E XP ER I ME NTAL C E LL RE S E ARCH

two different receptors for TNF-α, its effect on hematopoiesis is dual: TNFR-I (p55) mainly exerts the effects of TNF-α on GMPs, while TNFR-II (p75) is essential in signaling inhibition of primitive progenitors [45]. However, both receptors are involved in the inhibitory effects seen on HSCs and erythropoiesis [48,49]. Importantly, overproduction of TNF-α is associated with different hematopoietic disorders such as myelodysplastic syndrome, AML, and aplastic anemia [50–52]. >Next to TNF-α, interferons also have a major impact on hematopoiesis. Type I interferons (IFN-α and IFN-β) are rapidly produced upon viral infection and inhibit hematopoietic colony formation in vitro [53]. In line with these observations, type I interferons are responsible for the strong reduction in HSPC numbers following a viral infection and the ensuing pancytopenia [54]. Treatment of (noninfected) mice with IFN-α awakes quiescent HSCs to exit G0 and enter cell cycle, though chronic IFN stimulation would exhaust the HSC pool [20,22]. These IFN-α treated HSCs are outcompeted by untreated HSCs in competitive repopulation assays, because the former are functionally impaired and primed for apoptosis [20]. Yet, it has recently been shown that type I IFN-driven proliferation of HSCs in vivo is transient, and although chronic exposure causes BM aplasia, it does not lead to exhaustion of the HSC pool. Instead, IFN-exposed HSCs return to a quiescent state, which can protect them from apoptosis [55]. Type II interferon (interferon-γ; IFN-γ) has long been known to influence hematopoiesis in both humans and mice at various levels, though the underlying mechanisms have only recently been elucidated. Early studies have shown that IFN-γ negatively affects the in vitro colony formation and self-renewal capacity of isolated HSCs either by inducing differentiation or apoptosis [47,53,56,57]. We could corroborate these data and demonstrate that IFN-γ inhibits in a direct manner the self-renewal of HSCs in vivo following viral infection [58]. IFN-γ was found to induce suppressor of cytokine signaling-1 (SOCS1) in HSCs, which can inhibit the signal transducer and activator of transcription (STAT) 5-mediated signaling of the self-renewal inducing cytokine thrombopoietin and thereby alter key mediators of cell division [58]. Interestingly, IFN-γ does enhance the differentiation of more downstream progenitors and thereby enables the body to cope with the increased demand for immune cells [58,59]. IFN-γ also has a strong negative effect on erythropoiesis and plays an important role in the development of anemia of chronic diseases (ACD) [60]. We found that IFN-γ production in vivo induces ACD in mice, both through a reduction in the life span of circulating erythrocytes and through impaired erythropoiesis in the BM [61]. The latter could be attributed to an IRF-1 mediated upregulation in CMPs of the myeloid transcription factor PU.1 [61], which counteracts the function of the erythroid transcription factor GATA-1 [62]. We postulate that when IFN-γ is produced during inflammatory conditions, it induces the expression of PU.1 in progenitor cells, thereby inhibiting erythropoiesis and shifting hematopoiesis towards myelopoiesis. Interestingly, extramedullary erythropoiesis in the spleen is not sensitive to IFN-γ [63]. Although the underlying mechanism is not yet known, it may signify a compartmentalization of hematopoiesis during IFN-γ driven inflammation, in which erythropoiesis occurs mostly in the spleen and myelopoiesis in the BM. Regarding the latter, IFN-γ predominantly stimulates the formation of monocytes, possibly through the induction of PU.1 and IRF-8 in progenitor cells [64], whereas the formation of other hematopoietic lineages, such as neutrophilic [64] and eosinophilic [65] granulocytes, as well as B cells [66,67] is largely inhibited by IFN-γ. Also here may be an important role for SOCS-mediated inhibition of cytokine-induced

3 29 (2 014 ) 23 9 –247

STAT-signaling, as IFN-γ inhibits G-CSF-induced neutrophil differentiation through SOCS-3 [64] and IL-7-induced B cell formation through SOCS-1 [68]. As IFN-γ is mostly produced during viral infections, we postulate that the main function of IFN-γ in the BM is to boost the formation of monocytes for the generation of macrophages and inflammatory dendritic cells, at the cost of other, less relevant, cell types (reviewed in [69]). This will boost anti-viral immunity in the acute phase, but may lead to anemia and BM failure if this inflammatory feedback persists, which is seen during chronic infections. Another important and pleiotropic cytokine that can also act on the hematopoietic process is IL-1, as it can induce proliferation of HSCs in vitro and is necessary for the induction of granulopoieis in vivo [70]. However, IL-1-mediated expansion of hematopoietic progenitors in vivo occurs in an indirect fashion, as proliferation of HSCs, MPPs and GMPs, and accelerated output of granulocytes upon alum injection is dependent on IL-1R expressing radiation-resistant, nonhematopoietic cells [70]. Also IL-17 has been implicated to affect hematopoiesis indirectly: by modulating the expression of soluble and membrane-bound factors of BM stromal cells, IL-17 can induce HSPCs proliferation, enhance granulopoiesis and stimulate the formation of early stage erythroid progenitors, whereas outgrowth of late-stage erythroid progenitors is inhibited (reviewed in [71]). In conclusion, several pro-inflammatory cytokines not only mediate immune responses at the site of infection, but also have an important direct impact on hematopoiesis in general, and hematopoietic lineage choices in particular (Table 1). Most of the aforementioned cytokines can be produced by effector and memory T cells, which are known to enter the BM parenchyma [72]. We therefore speculate that BM T cells play a major role in skewing the hematopoietic output upon infection through local cytokine release inside the BM.

Conclusions and implications Taken all together, an accumulating number of studies provide evidence that pathogens and activated immune cells can directly affect hematopoietic processes in the BM. In line with the activation of naïve T cells, we here propose that HSPC differentiation during immune activation is also driven by 3 comparable signals (Fig. 1). Signal 1 is in this case provided by pathogens and danger signals, which awakes HSCs from their quiescent state, induces proliferation and lineage-specific transcriptional programs that drive differentiation. By ligation of costimulatory receptors on the surface of HSPCs, the induction of lineage commitment can be directly influenced by activated immune cells (Signal 2). In addition, activated immune cells can further modulate differentiation of hematopoietic progenitors by the production of pro-inflammatory cytokines (Signal 3). In sharp contrast to T cells, where Signal 1 is required for activation, various in vitro and in vivo studies show that both costimulatory molecules and pro-inflammatory cytokines can independently affect HSPC behavior without the explicit requirement for PAMP- or DAMP-signaling. This implies that Signal 1 is not essential for the activation of HSCs during immuneadapted hematopoiesis. However, it is difficult to fully exclude the presence of PAMPs (e.g. contamination of reagents with LPS) and DAMPs (e.g. dying cells) in these experimental set-ups. Moreover, it is highly likely that crosstalk or synergy between the three signals does occur in vivo upon infection, in particular because PAMPs can induce the upregulation of costimulatory molecules and

E XP E RI ME N TAL CE L L R ES E ARC H

pro-inflammatory cytokines. Though the interdependency of these 3 distinct signals during inflammatory stress in the BM and the functional impact of their convergence on HSPCs requires further investigation. Another layer of complexity is added to the model by the fact that both pathogens and activated immune cells not only interact directly with HSPCs, but also deliver pro-inflammatory signals to hematopoietic niche cells that influence HSPC behavior. TLRs, costimulatory molecules and inflammatory cytokine receptors are also found on (mesenchymal) stromal cells and resident immune cells within the niche. Upon triggering of these receptors on niche cells, a variety of pro-inflammatory cytokines, chemokines and signaling molecules can be produced or expressed that are capable of affecting hematopoiesis in an indirect manner [73–76]. The here described model thus implies that hematopoiesis during immune activation is a dynamic system in which a variety of activating and inhibiting signals of both homeostatic and inflammatory origin are integrated to induce a transcriptional program that allows the generation of appropriate BM output to fight invading pathogens. Elucidating how extrinsic stimulatory and inhibitory signals further downstream are integrated into one message within progenitor cells will gain useful insight in the complexity of lineage commitment and allow for strategies to manipulate hematopoiesis both in vitro and in vivo. Up until now the expression and function of only a small number of PRRs, danger-signals, costimulatory molecules and pro-inflammatory cytokines on HSPCs have been described, though there is an abundance of molecules produced upon infection of which the influence on hematopoiesis is still largely unknown. Additional studies should thus be undertaken to gain a full overview on which other inflammatory molecules can affect hematopoiesis and what their function is regarding the induction of lineage commitment. In addition, these studies could give useful insights in how proinflammatory molecules can be clinically used to boost hematopoiesis to combat (chronic) infections or rather targeted to prevent or ameliorate the development of inflammation-induced anemia and cytopenias.

Acknowledgments MAN is supported by the Landsteiner Foundation for Blood Transfusion Research (LSBR Fellowship #1014). For this review we were limited in the number of words and references we could use and given the breadth of the topics we discussed, we were obliged to make a selection of the papers that we would refer to. Hence, we apologize to those authors whom relevant work we did not refer to in this review.

references [1] M. Ogawa, Stochastic model revisited, Int. J. Hematol. 69 (1999) 2–5. [2] S.J. Morrison, D.T. Scadden, The bone marrow niche for haematopoietic stem cells, Nature 505 (2014) 327–334. [3] R. Schofield, The relationship between the spleen colony-forming cell and the haemopoietic stem cell, Blood Cells 4 (1978) 7–25. [4] L.D. Wang, A.J. Wagers, Dynamic niches in the origination and differentiation of haematopoietic stem cells, Nat. Rev. Mol. Cell Biol. 12 (2011) 643–655.

32 9 (2 014 ) 2 39 – 247

245

[5] L. Ding, S.J. Morrison, Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches, Nature 495 (2013) 231–235. [6] A. Greenbaum, Y.M. Hsu, R.B. Day, L.G. Schuettpelz, M.J. Christopher, J.N. Borgerding, T. Nagasawa, D.C. Link, CXCL12 in early mesenchymal progenitors is required for haematopoietic stemcell maintenance, Nature 495 (2013) 227–230. [7] K.Y. King, M.A. Goodell, Inflammatory modulation of HSCs: viewing the HSC as a foundation for the immune response, Nat. Rev. Immunol. 11 (2011) 685–692. [8] H. Takizawa, S. Boettcher, M.G. Manz, Demand-adapted regulation of early hematopoiesis in infection and inflammation, Blood 119 (2012) 2991–3002. [9] K. Tokoyoda, S. Zehentmeier, A.N. Hegazy, I. Albrecht, J.R. Grun, M. Lohning, A. Radbruch, Professional memory CD4þ T lymphocytes preferentially reside and rest in the bone marrow, Immunity 30 (2009) 721–730. [10] M. Feuerer, P. Beckhove, N. Garbi, Y. Mahnke, A. Limmer, M. Hommel, G.J. Hammerling, B. Kyewski, A. Hamann, V. Umansky, V. Schirrmacher, Bone marrow as a priming site for T-cell responses to blood-borne antigen, Nat. Med. 9 (2003) 1151–1157. [11] L.L. Cavanagh, R. Bonasio, I.B. Mazo, C. Halin, G. Cheng, A.W. van der Velden, A. Cariappa, C. Chase, P. Russell, M.N. Starnbach, P.A. Koni, S. Pillai, W. Weninger, U.H. von Andrian, Activation of bone marrow-resident memory T cells by circulating, antigen-bearing dendritic cells, Nat. Immunol. 6 (2005) 1029–1037. [12] D. Duffy, H. Perrin, V. Abadie, N. Benhabiles, A. Boissonnas, C. Liard, B. Descours, D. Reboulleau, O. Bonduelle, B. Verrier, R.N. van, C. Combadiere, B. Combadiere, Neutrophils transport antigen from the dermis to the bone marrow, initiating a source of memory CD8þ T cells, Immunity 37 (2012) 917–929. [13] A. Sapoznikov, Y. Pewzner-Jung, V. Kalchenko, R. Krauthgamer, I. Shachar, S. Jung, Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches, Nat. Immunol. 9 (2008) 388–395. [14] M.A. Schmid, H. Takizawa, D.R. Baumjohann, Y. Saito, M.G. Manz, Bone marrow dendritic cell progenitors sense pathogens via Toll-like receptors and subsequently migrate to inflamed lymph nodes, Blood 118 (2011) 4829–4840. [15] M.L. Kapsenberg, Dendritic-cell control of pathogen-driven T-cell polarization, Nat. Rev. Immunol. 3 (2003) 984–993. [16] H. Takizawa, R.R. Regoes, C.S. Boddupalli, S. Bonhoeffer, M.G. Manz, Dynamic variation in cycling of hematopoietic stem cells in steady state and inflammation, J. Exp. Med. 208 (2011) 273– 284. [17] B.L. Esplin, T. Shimazu, R.S. Welner, K.P. Garrett, L. Nie, Q. Zhang, M.B. Humphrey, Q. Yang, L.A. Borghesi, P.W. Kincade, Chronic exposure to a TLR ligand injures hematopoietic stem cells, J. Immunol. 186 (2011) 5367–5375. [18] Y. Nagai, K.P. Garrett, S. Ohta, U. Bahrun, T. Kouro, S. Akira, K. Takatsu, P.W. Kincade, Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment, Immunity 24 (2006) 801–812. [19] J.L. Zhao, C. Ma, R.M. O’Connell, A. Mehta, R. DiLoreto, J.R. Heath, D. Baltimore, Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis, Cell Stem Cell 14 (2014) 445–459. [20] M.A. Essers, S. Offner, W.E. Blanco-Bose, Z. Waibler, U. Kalinke, M.A. Duchosal, A. Trumpp, IFNalpha activates dormant haematopoietic stem cells in vivo, Nature 458 (2009) 904–908. [21] C. Frelin, R. Herrington, S. Janmohamed, M. Barbara, G. Tran, C.J. Paige, P. Benveniste, J.C. Zuniga-Pflucker, A. Souabni, M. Busslinger, N.N. Iscove, GATA-3 regulates the self-renewal of long-term hematopoietic stem cells, Nat. Immunol. 14 (2013) 1037–1044. [22] T. Sato, N. Onai, H. Yoshihara, F. Arai, T. Suda, T. Ohteki, Interferon regulatory factor-2 protects quiescent hematopoietic stem cells

246

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38] [39]

[40]

E XP ER I ME NTAL C E LL RE S E ARCH

from type I interferon-dependent exhaustion, Nat. Med. 15 (2009) 696–700. R.S. Welner, R. Pelayo, Y. Nagai, K.P. Garrett, T.R. Wuest, D.J. Carr, L.A. Borghesi, M.A. Farrar, P.W. Kincade, Lymphoid precursors are directed to produce dendritic cells as a result of TLR9 ligation during herpes infection, Blood 112 (2008) 3753–3761. K. De Luca, V. Frances-Duvert, M.J. Asensio, R. Ihsani, E. Debien, M. Taillardet, E. Verhoeyen, C. Bella, S. Lantheaume, L. Genestier, T. Defrance, The TLR1/2 agonist PAM(3)CSK(4) instructs commitment of human hematopoietic stem cells to a myeloid cell fate, Leukemia 23 (2009) 2063–2074. M. Sioud, Y. Floisand, L. Forfang, F. Lund-Johansen, Signaling through toll-like receptor 7/8 induces the differentiation of human bone marrow CD34þ progenitor cells along the myeloid lineage, J. Mol. Biol. 364 (2006) 945–954. D.T. Starczynowski, A. Karsan, Innate immune signaling in the myelodysplastic syndromes, Hematol./Oncol. Clin. N. Am. 24 (2010) 343–359. A. Khosravi, A. Yanez, J.G. Price, A. Chow, M. Merad, H.S. Goodridge, S.K. Mazmanian, Gut microbiota promote hematopoiesis to control bacterial infection, Cell Host Microbe 15 (2014) 374–381. M. Velegraki, H. Koutala, C. Tsatsanis, H.A. Papadaki, Increased levels of the high mobility group box 1 protein sustain the inflammatory bone marrow microenvironment in patients with chronic idiopathic neutropenia via activation of toll-like receptor 4, J. Clin. Immunol. 32 (2012) 312–322. M. Hofer, M. Pospisil, L. Weiterova, Z. Hoferova, The role of adenosine receptor agonists in regulation of hematopoiesis, Molecules 16 (2011) 675–685. J. Cho, R. Yusuf, S. Kook, E. Attar, D. Lee, B. Park, T. Cheng, D.T. Scadden, B.C. Lee, Purinergic P2Y14 receptor modulates stress-induced hematopoietic stem/progenitor cell senescence, J. Clin. Investig. 124 (2014) 3159–3171. A. Wiesmann, R.L. Phillips, M. Mojica, L.J. Pierce, A.E. Searles, G.J. Spangrude, I. Lemischka, Expression of CD27 on murine hematopoietic stem and progenitor cells, Immunity 12 (2000) 193– 199. M.A. Nolte, R. Arens, O.R. van, O.M. van, B. Hooibrink, R.A. van Lier, M.H. van Oers, Immune activation modulates hematopoiesis through interactions between CD27 and CD70, Nat. Immunol. 6 (2005) 412–418. C. Schurch, C. Riether, M.S. Matter, A. Tzankov, A.F. Ochsenbein, CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression, J. Clin. Investig. 122 (2012) 624–638. V. De Colvenaer, S. Taveirne, J. Hamann, A.M. de Bruin, S.M. De, T. Taghon, B. Vandekerckhove, J. Plum, L.R. van, G. Leclercq, Continuous CD27 triggering in vivo strongly reduces NK cell numbers, Eur. J. Immunol. 40 (2010) 1107–1117. S.W. Lee, Y. Park, T. So, B.S. Kwon, H. Cheroutre, R.S. Mittler, M. Croft, Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells, Nat. Immunol. 9 (2008) 917–926. D. Jiang, Y. Chen, H. Schwarz, CD137 induces proliferation of murine hematopoietic progenitor cells and differentiation to macrophages, J. Immunol. 181 (2008) 3923–3932. Q. Tang, D. Jiang, S. Alonso, A. Pant, J.M. Martinez Gomez, D.M. Kemeny, L. Chen, H. Schwarz, CD137 ligand signaling enhances myelopoiesis during infections, Eur. J. Immunol. 43 (2013) 1555–1567. U. Schonbeck, P. Libby, The CD40/CD154 receptor/ligand dyad, Cell. Mol. Life Sci. 58 (2001) 4–43. T. Seijkens, D. Engel, M. Tjwa, E. Lutgens, The role of CD154 in haematopoietic development, Thromb. Haemost. 104 (2010) 693–701. L. Flores-Romo, P. Bjorck, V. Duvert, K.C. van, S. Saeland, J. Banchereau, CD40 ligation on human cord blood CD34þ hematopoietic progenitors induces their proliferation and

3 29 (2 014 ) 23 9 –247

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

differentiation into functional dendritic cells, J. Exp. Med. 185 (1997) 341–349. A. Solanilla, J. Dechanet, A.A. El, M. Dupouy, F. Godard, J. Chabrol, P. Charbord, J. Reiffers, A.T. Nurden, B. Weksler, J.F. Moreau, J. Ripoche, CD40-ligand stimulates myelopoiesis by regulating flt3-ligand and thrombopoietin production in bone marrow stromal cells, Blood 95 (2000) 3758–3764. I. Mavroudi, H.A. Papadaki, The role of CD40/CD40 ligand interactions in bone marrow granulopoiesis, Sci. World J. 11 (2011) 2011–2019. J. Zhu, S.G. Emerson, Hematopoietic cytokines, transcription factors and lineage commitment, Oncogene 21 (2002) 3295– 3313. D. Bryder, V. Ramsfjell, I. Dybedal, K. Theilgaard-Monch, C.M. Hogerkorp, J. Adolfsson, O.J. Borge, S.E. Jacobsen, Self-renewal of multipotent long-term repopulating hematopoietic stem cells is negatively regulated by Fas and tumor necrosis factor receptor activation, J. Exp. Med. 194 (2001) 941–952. F.W. Jacobsen, M. Rothe, L. Rusten, D.V. Goeddel, E.B. Smeland, O.P. Veiby, L. Slordal, S.E. Jacobsen, Role of the 75-kDa tumor necrosis factor receptor: inhibition of early hematopoiesis, Proc. Natl. Acad. Sci. USA 91 (1994) 10695–10699. Y. Zhang, A. Harada, H. Bluethmann, J.B. Wang, S. Nakao, N. Mukaida, K. Matsushima, Tumor necrosis factor (TNF) is a physiologic regulator of hematopoietic progenitor cells: increase of early hematopoietic progenitor cells in TNF receptor p55deficient mice in vivo and potent inhibition of progenitor cell proliferation by TNF alpha in vitro, Blood 86 (1995) 2930–2937. C. Selleri, T. Sato, S. Anderson, N.S. Young, J.P. Maciejewski, Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death, J. Cell. Physiol. 165 (1995) 538–546. C.J. Pronk, O.P. Veiby, D. Bryder, S.E. Jacobsen, Tumor necrosis factor restricts hematopoietic stem cell activity in mice: involvement of two distinct receptors, J. Exp. Med. 208 (2011) 1563–1570. L.S. Rusten, S.E. Jacobsen, Tumor necrosis factor (TNF)-alpha directly inhibits human erythropoiesis in vitro: role of p55 and p75 TNF receptors, Blood 85 (1995) 989–996. G. Stifter, S. Heiss, G. Gastl, A. Tzankov, R. Stauder, Overexpression of tumor necrosis factor-alpha in bone marrow biopsies from patients with myelodysplastic syndromes: relationship to anemia and prognosis, Eur. J. Haematol. 75 (2005) 485–491. T. Hara, K. Ando, H. Tsurumi, H. Moriwaki, Excessive production of tumor necrosis factor-alpha by bone marrow T lymphocytes is essential in causing bone marrow failure in patients with aplastic anemia, Eur. J. Haematol. 73 (2004) 10–16. S.D. Mundle, A. Ali, J.D. Cartlidge, S. Reza, S. Alvi, M.M. Showel, B.Y. Mativi, V.T. Shetty, P. Venugopal, S.A. Gregory, A. Raza, Evidence for involvement of tumor necrosis factor-alpha in apoptotic death of bone marrow cells in myelodysplastic syndromes, Am. J. Hematol. 60 (1999) 36–47. H.E. Broxmeyer, L. Lu, E. Platzer, C. Feit, L. Juliano, B.Y. Rubin, Comparative analysis of the influences of human gamma, alpha and beta interferons on human multipotential (CFU-GEMM), erythroid (BFU-E) and granulocyte-macrophage (CFU-GM) progenitor cells, J. Immunol. 131 (1983) 1300–1305. D. Binder, J. Fehr, H. Hengartner, R.M. Zinkernagel, Virus-induced transient bone marrow aplasia: major role of interferon-alpha/ beta during acute infection with the noncytopathic lymphocytic choriomeningitis virus, J. Exp. Med. 185 (1997) 517–530. E.M. Pietras, R. Lakshminarasimhan, J.M. Techner, S. Fong, J. Flach, M. Binnewies, E. Passegue, Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons, J. Exp. Med. 211 (2014) 245–262.

E XP E RI ME N TAL CE L L R ES E ARC H

[56] H.W. Snoeck, D.R. Van Bockstaele, G. Nys, M. Lenjou, F. Lardon, L. Haenen, I. Rodrigus, M.E. Peetermans, Z.N. Berneman, Interferon gamma selectively inhibits very primitive CD342þCD38  and not more mature CD34þCD38þ human hematopoietic progenitor cells, J. Exp. Med. 180 (1994) 1177–1182. [57] L. Yang, I. Dybedal, D. Bryder, L. Nilsson, E. Sitnicka, Y. Sasaki, S.E. Jacobsen, IFN-gamma negatively modulates self-renewal of repopulating human hemopoietic stem cells, J. Immunol. 174 (2005) 752–757. [58] A.M. de Bruin, O. Demirel, B. Hooibrink, C.H. Brandts, M.A. Nolte, Interferon-gamma impairs proliferation of hematopoietic stem cells in mice, Blood 121 (2013) 3578–3585. [59] M.T. Baldridge, K.Y. King, N.C. Boles, D.C. Weksberg, M.A. Goodell, Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection, Nature 465 (2010) 793–797. [60] G. Weiss, L.T. Goodnough, Anemia of chronic disease, N. Engl. J. Med. 352 (2005) 1011–1023. [61] S.F. Libregts, L. Gutiérrez, A.M. de Bruin, F. Wensveen, P. Papadopoulos, W. van IJcken, Z. Özgür, S. Philipsen, M.A. Nolte, Chronic IFNγ production in mice induces anemia by reducing erythrocyte lifespan and inhibiting erythropoiesis through an IRF-1/PU.1-axis, Blood 118 (2011) 2578–2588. [62] N. Rekhtman, F. Radparvar, T. Evans, A.I. Skoultchi, Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells, Genes Dev. 13 (1999) 1398–1411. [63] S. Millot, V. Andrieu, P. Letteron, S. Lyoumi, M. Hurtado-Nedelec, Z. Karim, O. Thibaudeau, S. Bennada, J.L. Charrier, S. Lasocki, C. Beaumont, Erythropoietin stimulates spleen BMP4-dependent stress erythropoiesis and partially corrects anemia in a mouse model of generalized inflammation, Blood 116 (2010) 6072–6081. [64] A.M. de Bruin, S.F. Libregts, M. Valkhof, L. Boon, I.P. Touw, M.A. Nolte, IFNgamma induces monopoiesis and inhibits neutrophil development during inflammation, Blood 119 (2012) 1543–1554. [65] A.M. de Bruin, M. Buitenhuis, K.F. van der Sluijs, K.P. van Gisbergen, L. Boon, M.A. Nolte, Eosinophil differentiation in the bone marrow is inhibited by T cell-derived IFN-gamma, Blood 116 (2010) 2559–2569. [66] H.A. Young, D.M. Klinman, D.A. Reynolds, K.J. Grzegorzewski, A. Nii, J.M. Ward, R.T. Winkler-Pickett, J.R. Ortaldo, J.J. Kenny,

32 9 (2 014 ) 2 39 – 247

[67]

[68]

[69]

[70]

[71]

[72] [73]

[74]

[75]

[76]

247

K.L. Komschlies, Bone marrow and thymus expression of interferon-gamma results in severe B-cell lineage reduction, T-cell lineage alterations, and hematopoietic progenitor deficiencies, Blood 89 (1997) 583–595. R. Arens, K. Tesselaar, P.A. Baars, G.M. van Schijndel, J. Hendriks, S.T. Pals, P. Krimpenfort, J. Borst, M.H. van Oers, R.A. van Lier, Constitutive CD27/CD70 interaction induces expansion of effector-type T cells and results in IFNgamma-mediated B cell depletion, Immunity 15 (2001) 801–812. S.A. Corfe, R. Rottapel, C.J. Paige, Modulation of IL-7 thresholds by SOCS proteins in developing B lineage cells, J. Immunol. 187 (2011) 3499–3510. A.M. de Bruin, C. Voermans, M.A. Nolte, Impact of interferongamma on hematopoiesis, Blood(2014), http://dx.doi.org/ 10.1182/blood-2014-04-568451 (e-pub ahead of print). Y. Ueda, D.W. Cain, M. Kuraoka, M. Kondo, G. Kelsoe, IL-1R type I-dependent hemopoietic stem cell proliferation is necessary for inflammatory granulopoiesis and reactive neutrophilia, J. Immunol. 182 (2009) 6477–6484. A. Krstic, S. Mojsilovic, G. Jovcic, D. Bugarski, The potential of interleukin-17 to mediate hematopoietic response, Immunol. Res. 52 (2012) 34–41. F. Di Rosa, R. Pabst, The bone marrow: a nest for migratory memory T cells, Trends Immunol. 26 (2005) 360–366. M. Pevsner-Fischer, V. Morad, M. Cohen-Sfady, L. Rousso-Noori, A. Zanin-Zhorov, S. Cohen, I.R. Cohen, D. Zipori, Toll-like receptors and their ligands control mesenchymal stem cell functions, Blood 109 (2007) 1422–1432. S.L. Tomchuck, K.J. Zwezdaryk, S.B. Coffelt, R.S. Waterman, E.S. Danka, A.B. Scandurro, Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses, Stem Cells 26 (2008) 99–107. C. Shi, T. Jia, S. Mendez-Ferrer, T.M. Hohl, N.V. Serbina, L. Lipuma, I. Leiner, M.O. Li, P.S. Frenette, E.G. Pamer, Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating toll-like receptor ligands, Immunity 34 (2011) 590–601. C.M. Schurch, C. Riether, A.F. Ochsenbein, Cytotoxic CD8 T cells stimulate hematopoietic progenitors by promoting cytokine release from bone marrow mesenchymal stromal cells, Cell Stem Cell 14 (2014) 460–472.