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-Induced Changes in Hematopoiesis Arielle Glatman Zaretsky, Julie B. Engiles and Christopher A. Hunter This information is current as J Immunol 2014; 192:27-33; ; of September 29, 2021. doi: 10.4049/jimmunol.1302061 http://www.jimmunol.org/content/192/1/27 Downloaded from References This article cites 104 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/192/1/27.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology

Infection-Induced Changes in Hematopoiesis Arielle Glatman Zaretsky,* Julie B. Engiles,† and Christopher A. Hunter* The (BM) is an important site for the in- of lineage commitments. Lineageneg Sca-1+ c-kit+ cells (LSKs; terrelated processes of hematopoiesis, , reviewed extensively in Refs. 7–9) include the earliest hema- , and . A wide variety of mi- topoietic precursors in the BM with the potential to develop crobial challenges are associated with profound changes into multiple lineage-specific progenitors, such as common in this compartment that impact on hematopoietic dif- lymphoid and myeloid progenitors and or ferentiation and mobilization of a variety of cell types. erythrocytic precursors (Fig. 1). Notably, only a small per- This article reviews some of the key pathways that con- centage of LSKs are HSCs; the majority of the LSK population trol BM homeostasis, the infectious and inflammatory represents a variety of multipotent or lineage committed cells. At steady-state, this differentiation is a complex but well-ordered

processes that affect the BM, and how addressing the Downloaded from knowledge gaps in this area has the potential to widen process, leading to the development of , gran- our comprehension of immune homeostasis. The Journal ulocytes, and myeloid cells. of Immunology, 2014, 192: 27–33. Given the diverse functions of the BM, it is not surprising that this organ is composed of distinct anatomical compartments. For example, within the BM, HSCs are distributed primarily in or he bone marrow (BM) is a critical site of immune cell near the endosteal region or the interface between medullary http://www.jimmunol.org/ development and erythropoiesis, and provides a niche bone and stromal cells (Fig. 1). This is a site with a distinctive T for plasma cells and memory T cells. Although the cell microanatomic , although recent evidence populations and structural elements in the BM are typically indicates that perivascular niches also support HSC populations characterized by composition and morphology (1, 2), the ap- (6). The retention of HSCs in this environment is thought to plication of novel imaging technologies, such as intravital im- promote survival and/or maintain hematopoietic progenitors in aging and laser-scanning cytometry, has allowed the field to the quiescent G0 phase of the cell cycle, allowing these cells to better define the microenvironments within this complex organ. self-renew and offering a ready pool of cells for rapid emer- Similarly, the use of conditional knockout technologies has gence (10–12). The direct interactions between vascular stromal helped to clarify the factors that maintain stem cell populations cells and nestin-negative mesenchymal progenitors, and be- by guest on September 29, 2021 and support the development of hematopoietic precursors and tween osteoblastic cells and HSCs themselves, promote HSC immature B cells (3–6). Using these advances, recent subsetting survival and control niche size (5, 13). of stromal and precursor populations in the BM has provided Several and molecules, notably CXCL12 insights into their behavior in the endosteal and perivascular and VLA-4 (14), contribute to HSC localization and main- compartments (3–6). In addition to the central role of the BM in tenance, and the local production of by mes- maintaining immune homeostasis, the ability to generate and enchymal and perivascular stromal cells, as well as endothelial mobilize immune cells in response to infection is a key function cells, promotes the generation and maintenance of HSCs (6). of this system. Notably, emergency granulopoiesis and rapid Perhaps the best studied –receptor pair in this pro- mobilization of from the BM is key for resistance cess is CXCL12–CXCR4, and disruption of this pathway leads to many . Similarly, increased erythropoiesis can be to alterations in cellular retention in the BM, including mo- a physiological response to inflammation, but certain in- bilization of early lymphoid progenitors and HSCs (14, 15). fections lead to the depletion of erythroid precursors and the However, these cell types occupy distinct niches, populated by development of anemia. The overarching goal of this review is to discrete populations of CXCL12-producing cells (16). Thus, discuss the role of the BM niche in the host response to infection, expression of CXCL12 by endothelial cells, perivascular stromal illustrate the impact of infectious on this compart- cells, and osteoblasts supports specific cell types within dis- ment, and highlight some of the major questions in the field. tinct niches. For example, the use of lineage-specific deletions Hematopoiesis and the niche established that nestin-negative mesenchymal progenitors, not Hematopoiesis is the process by which hematopoietic stem CXCL12-abundant reticular cells (which make the majority of cells (HSCs) differentiate into immune cells through a series CXCL12) (12, 17, 18), are the critical source of CXCL12

*Department of Pathobiology, School of Veterinary Medicine, University of Pennsylva- 380 South University Avenue, Room 313 Hill Pavilion, Philadelphia, PA 19104. nia, Philadelphia, PA 19104; and †New Bolton Center, Kennett Square, PA 19348 E-mail address: [email protected] Received for publication August 2, 2013. Accepted for publication October 30, 2013. Abbreviations used in this article: BM, bone marrow; HSC, hematopoietic stem cell; LSK, lineageneg Sca-1+ c-kit+ cell; Treg, regulatory . This work was supported by the National Institutes of Health (Grants AI 042334 and T32 AI 055400), the American Foundation, and the Commonwealth of Pennsylvania. Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 Address correspondence and reprint requests to Dr. Christopher A. Hunter. Depart- ment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania,

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302061 28 BRIEF REVIEWS: INFECTION-INDUCED CHANGES IN HEMATOPOIESIS

FIGURE 1. HSC responses to infection. (A–C) Po- tential routes of sensing by HSCs. (A) HSCs in the BM can express pattern recognition receptors, such as TLRs; thus, when the BM is directly infected, these cells may recognize pathogen-derived Ag or immune products produced in response to infection within the BM. Alter- natively, circulating HSCs in the expressing pattern recognition receptors may recognize pathogen associated molecular patterns and traffic back to the BM to relay these signals. (B) HSCs in the BM may be directly infected by pathogens, such as JC and respond directly to this challenge. (C) produced at distal sites, such as IFN-g or type I IFNs, may enter the BM and signal HSCs to initiate BM responses. Infection-induced changes in the BM (D). HSCs are maintained by stromal cells and CXCL12–CXCR4 interactions. Although HSCs are de- picted in endosteal regions, there is also evidence for their

presence in perivascular niches. These cells can differ- Downloaded from entiate into myeloid or common lymphoid progenitors, which then undergo , granulopoiesis, and/or lymphopoiesis. The impact of infection on these processes is shown, with increased myelopoiesis and emergency granulopoiesis correlating with decreased lymphopoiesis. http://www.jimmunol.org/

required to maintain HSCs in the BM niche (11). This study Notably, some of the responses associated with diverse in- also demonstrated that other stromal cells are key sources of fections are context dependent, which likely reflects different CXCL12 required for survival of progenitors. Of note, host–pathogen interactions. Thus, whether a pathogen can pre-B, pro-B, and mature B cells, as well as , ex- establish infection in the BM and which cell types it infects are press high levels of CXCR4, although mature and immature relevant factors. This has led to an interest in understanding B cell subsets are the least responsive to CXCL12. These dif- whether HSCs are inherently resistant to infection (9); however, by guest on September 29, 2021 ferential sensitivities imply that later-stage B cell populations are many of these studies have used pathogens that do not com- poised to traffic out of the BM, whereas early-stage B cells are monly infect the BM or pathogens that typically require more receptive to signals that maintain their BM localization , a process that HSCs cannot perform. For in- (19). Understanding these events has led to the use of blocking stance, mycobacterial species can be isolated from the BM reagents for CXCL12 and CXCR4, which mobilize HSCs from under a variety of circumstances, which range from asymp- the BM, resulting in improved harvesting of stem cells for tomatic individuals to AIDS patients with overt clinical , transplantation (14, 17, 20). and a recent report highlighted that Mycobacterium Inflammation, infection, and hematopoiesis resides latently in mesenchymal stem cells, which are phagocytic (34). The importance of understanding these specifics is ex- It has long been recognized that systemic infection with a emplified by the disparate responses associated with different variety of bacterial, viral, and parasitic organisms can result in . Thus, the presence of the noncytolytic lymphocytic profound alterations in the BM, many of which appear to be choriomeningitis virus in the BM contributes to the reduced part of a conserved host response to microbial challenge (Fig. 1). For example, during malaria and toxoplasmosis (and other ability of HSCs to engraft in this site (35, 36). JC virus, the systemic challenges), there is an increase in granulocytes in the of progressive multifocal leukoencephalopathy in im- BM, but a transient decrease in the numbers of lymphocytes, munocompromised patients, can infect HSCs and B cells, erythrocytes, and , despite low parasite bur- and is known to persist within the BM. Notably, several Ab- mediated therapies in humans that target LFA-1, VLA-4, or dens in this site (21–24). Increased populations of LSKs + and/or HSCs in the BM are the hallmark of many experi- CD20 lead to mobilization of pre-BandBcellsandCD34 mental (25–31). Thus, challenge with Plasmodium HSC progenitors from the BM. It has been proposed that in chabaudi or Pneumocystis carinii, organisms not typically found the context of reduced immune surveillance, these events in the BM, leads to increased LSK and HSC populations in the promote the dissemination of JC virus to the brain (37, 38). BM and circulation, followed by an increase in multipotent CMV can also infect stromal and mononuclear cells within progenitor cells (25, 26). Similarly, murine ehrlichiosis results in the BM, which has been linked to a reduced ability to make increased numbers of LSKs, although these cells appear to have progenitor colonies (39). Although the examples discussed a defect in their ability to differentiate (32, 33). For many earlier focus on organisms found in the BM during infection, of these examples, it is unclear whether these alterations are reductions in precursor populations can also occur with in- secondary consequences of systemic inflammation or part of fectious challenges that do not establish in this site. For ex- a coordinated host response to limit infection. ample, marked decreases in CD34+ hematopoietic precursors The Journal of Immunology 29 have been reported during HIV and SIV infection without parasite of mice that is restricted to the gut, this challenge detection of local virus (40–43). leadstoepithelialcellproductionofthymicstromallym- Whether HSCs have an active role in immune sensing phopoietin that induces production in the BM (57). remains an open question (Fig. 1), and it has been proposed In contrast, increased numbers are characteristic that the expansion of HSC populations may serve as a com- of many bacterial infections, and G-CSF promotes “emergency ponent of the primary response, as well as a mechanism to granulopoiesis” in the BM (58, 59). At the molecular level, replenish depleted progenitor populations (9). In adults, small steady-state granulopoiesis is regulated through the transcrip- numbers of HSCs appear to traffic between the BM and cir- tion factor C/EBPa, whereas C/EBPb and STAT3 mediate G- culation, perhaps acting as a form of immune surveillance that CSF–dependent granulopoiesis (60, 61). Naive mice depleted can relay distal signals to the BM (44, 45). Evidence in favor of of neutrophils or injected with the adjuvant alum (which surveillance activity includes HSC expression of TLRs (Fig. 1) induces mobilization) exhibit emergency gran- (9). Furthermore, TLR signaling in LSKs and other hemato- ulopoiesis and proliferation of HSCs in a G-CSF– and poietic progenitors results in myeloid differentiation (46), C/EBPb–dependent manner (62). This body of work illustrates whereas TLR9 is required in a model of HSV-1 infection for the feedback mechanisms that allow cells in the BM to respond HSCs to produce dendritic cells (47). There are studies in rapidly to changes in the periphery, and suggests the presence which MyD88, the adaptor molecule involved in TLR and IL-1 of a density-sensing mechanism that regulates granulopoietic signaling, has been shown to be critical for infection-induced activity (62). granulopoiesis, myelopoiesis, and mobilization of these pop- The BM is also an active site of myelopoiesis, leading to the Downloaded from ulations. Thus, infection with vaccinia virus in vivo or culture production of and . BM macrophages of LSKs with Candida albicans in vitro led to increased num- have an important role in maintaining the HSC niche (63), yet bers of LSKs and differentiated myeloid cells in the BM in an the populations that are mobilized in response to infection MyD88-dependent manner (27, 28). However, the observa- have key roles in the development and resolution of inflam- tion that the increase in LSKs present in a model of bacterial mation, as well as acting as potent effectors or infection with aureus is MyD88 (64). In mice challenged with T. gondii or Listeria mono- http://www.jimmunol.org/ independent (30) highlights the gaps in our understanding of cytogenes, the CCR2-dependent mobilization of monocytes the cross talk between the peripheral immune response and out of the BM is essential to control these organisms (64–67). the BM compartment. Nevertheless, this literature provides a During Ehrlichia infection, IFN-g is required to activate direct link between pathogen recognition and mobilization macrophages to control this intracellular bacterium, but IFN-g of the appropriate innate populations required to control also contributes to the diminished hematopoietic progenitor infection. population in the BM (33). Indeed, the ability of IFN-g to induce SOCS3 in granulocyte- progenitors leads Erythropoiesis

to reduced G-CSF signaling andashiftfromneutrophil by guest on September 29, 2021 The suppression of erythropoiesis and development of anemia production to myeloid differentiation (68). In this context, it is characteristic of many infections (48). For organisms, such is tempting to speculate that systemic IFN-g (or direct TLR as Plasmodium and Babesia sp., that directly infect erythro- signaling) provides a mechanism to tailor BM output to the cytes, there is a clear link to erythrocyte destruction that can class of pathogen. However, the identification of an IFN-g– eventually lead to a depletion of erythroid precursor cells in dependent atypical progenitor population of IL-7R+c-kithi a chronic setting. For other pathogens, such as the African cells, with predominantly myeloid potential, that is involved Trypanosomes, the presence of parasites in the bloodstream in clearance of P. chabaudi (26) illustrates the broad effects of is associated with damage of erythrocytes, elevated eryth- IFN-g on myelopoiesis. rophagocytosis, and ultimately, decreased erythropoiesis (49). In other settings, severe anemia associated with the loss of B cell lymphopoiesis and homeostasis erythroid precursors also has an immune component (50, 51); The BM is also a site of B cell development, and many in- Ehrlichia muris and Toxoplasma gondii do not infect eryth- fections can profoundly impact this process (47, 69–74). rocytes, but these distinct challenges lead to a reduction in Challenge with influenza or lymphocytic choriomeningitis erythroid precursors and severe anemia (32). Although the virus results in a transient decrease in pro-, pre-, and imma- cytokines IFN-g, IL-6, and IL-15 are implicated in immune- ture B cells in the BM, which is, in part, dependent on TNF-a mediated anemia (24, 52), it remains unclear whether this and a (71, 72). In a model of bacterial sepsis, the response simply reflects an interesting epiphenomenon or is early depletion of B cell progenitors is delayed in MyD88- part of a conserved host response that limits availability of deficient mice, indicating a role for TLR or IL-1 family mem- host cells for organisms that do infect erythrocytes. bers (30). Although the physiological significance of these events remains to be defined, the block in B cell development Granulopoiesis and myelopoiesis in the BM correlates with reduced humoral responses to irrelevant Ags Increased granulopoiesis within the BM is a hallmark of acute (71, 72). Interestingly, under inflammatory conditions, there infection or inflammation in experimental and clinical settings is an inverse correlation between the induction of granulopoiesis that gives rise to short-lived neutrophils, , and and decreased lymphopoiesis in the BM (75). In one experi- (21, 23, 32, 53–56). It has long been recognized mental system, treatment of mice with IFA results in an increase that increased circulating levels of basophils and eosinophils in granulocyte numbers, but a decline in the numbers of B (and are characteristic of many helminth parasites, but how the T) lymphocytes in the BM (76). Similarly, during infection with communicates with the BM to promote this the bacterium E. muris, a transient decrease in B220+ cells in the process has been unclear. For Trichuris muris, a nematode BM is accompanied by an increase in granulocytes (32). Insight 30 BRIEF REVIEWS: INFECTION-INDUCED CHANGES IN HEMATOPOIESIS into how these events may be coordinated is provided by the quired for HSC self-renewal, leading to a reduction in the observation that, although lymphoid and granulocytic precursors number of HSCs (94). express CXCR4, the disruption of the CXCL12/CXCR4 axis Systemic levels of IL-1 and TNF are also characteristic of during inflammation leads to preferential loss of B cell precursors, many infectious challenges and have been linked to alter- potentially providing space to generate additional granulocytes ations in the BM. TNF-a treatment results in a reduction required for resistance to infection (75). These studies highlight in progenitor populations in the BM, whereas IL- the coordinated changes that occur in hematopoietic processes 1b elicits increased granulocyte precursors (76). Moreover, in the BM during infection, which are presumably required to CXCR4-deficient mice or mice treated with pertussis , allow the development of appropriate responses to different which blocks chemokine signaling, given IL-1 or TNF-a have classes of pathogen. increased B cell and myeloid progenitors in the circulation, in- dicating that CXCR4–CXCL12 interactions facilitate - BM as a niche for plasma cells and memory T cells mediated regulation of B cell and myeloid cell retention in the a The BM also provides a niche for long-lived BM (76). In addition, TNF- and IL-1 (and RANKL and populations that continually produce Abs against previously M-CSF) can induce differentiation from mononuclear encountered Ags. The ability of eosinophils, basophils, meg- precursor cells and subsequent inflammatory osteolysis, a com- akaryocytes, and stromal cells in this site to produce BLyS, plication in many infectious, inflammatory, and neoplastic dis- April, IL-6, and CXCL12 is required for the survival and eases (96–98). Additional studies are required to understand the retention of plasma cells (3, 4, 77–83). As noted earlier, in- physiological significance of these cytokine-mediated changes in Downloaded from fection can lead to alterations in many of these cell populations, the BM and whether they impact on the development of im- and there is evidence that without eosinophils, alternative mune responses that are tailored to specific pathogens. plasma cell survival niches can be established in the spleen BM as an immune-privileged site (78). Memory CD4+ and CD8+ T cells also reside within the As described earlier, the BM can be a site of infection, but it is BM, maintained by stromal cells that produce the cytokines sensitive to the systemic effects of microbial challenge at distal http://www.jimmunol.org/ IL-7 and IL-15 that act as survival and proliferative factors for locations, and it is likely that these processes could be det- these populations (84–89). In humans, it has been shown rimentaltoessentialstemcellpopulations.Consequently, that memory T cells in the BM are more highly activated mechanisms to temper the adverse effects of inflammation on and polyfunctional than those isolated from blood, although different stem cell niches may be necessary. Although the BM memory T cells from blood can develop a similar phenotype lacks a physical barrier to exclude immune cells, there are after culture with IL-15 (87, 90). Thus far, it is unclear whether elements of immune privilege in this compartment that may the profound infection-induced changes in the BM impact on protect progenitors from immune-mediated damage or in- the (ill-defined) memory T cell and plasma cell niches or on the flammatory signals that could lead to transformation of these function of these populations. Understanding how different by guest on September 29, 2021 long-lived pluripotent cells. Notably, as much as ∼25% of infections influence the homeostasis of memory cell pop- BM CD4+ TcellsareFoxp3+ regulatory T cells (Tregs), a ulations in the BM may provide opportunities to manipulate much higher frequency than the 5–10% typically present these niches, and thus aid in the design of vaccines that induce in other sites. Intravital imaging of the BM of Foxp3-GFP long-lasting . reporters revealed that Tregs are predominantly located in or near the endosteal region, with the majority of HSCs found Impact of systemic cytokine responses on the BM compartment in close proximity to or in contact with Tregs (99). The Although some changes that occur in the BM during certain significance of these populations in infection has not been infections may be attributed to the local presence of pathogens, addressed; however, in an allogeneic transfer model, depletion perhaps the most common scenario is that the production of of Tregs prevented engraftment of an allo-HSC progenitor cytokines at distal sites affects the BM (Fig. 1) (91). Thus, type population (99). After BM transplantation, BM T cells ex- I IFNs can shift HSCs out of cell-cycle arrest and induce press a unique profile of surface markers and cytokine pro- proliferation and differentiation, ultimately resulting in de- duction, with high expression of CD44, CD62L, and CD45RB, creased numbers of HSCs (92). In murine models of influenza higher levels of IFN-g,IL-4,andIL-10,anddecreasedIL-2 or Sendai virus, production of type I IFNs in the leads to secretion, compared with those in other sites, and an in- upregulation of antiviral genes in hematopoietic cells in the creased ability to protect from graft-versus-host disease (100). BM (93). Whether these factors are produced at sufficiently Similar findings were reported in human patients, wherein high levels in the to have systemic effects in the BM or increased Tregs positively correlated with lower incidence whether there is a mechanism to relay these signals to the BM of graft-versus-host disease (100, 101). More recently, in is unclear. As discussed earlier, IFN-g can modify myelo- two models of arthritic disease, Tregs in the BM inhibited poiesis (26, 33, 68), and other aspects of hematopoiesis (94) TNF-mediated bone damage (102), as well as plasma cell and the high systemic levels of IFN-g characteristic of many accumulation (103). Taken together, these studies suggest infections suggest it would have a major impact on the BM. that the Treg population in the BM creates a suppressive During chronic infection with Mycobacterium avium,this environment, which establishes a specialized niche for HSCs. production of IFN-g can activate HSCs from the quiescent Although Treg populations at other sites can be significantly state (95). 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