EDITORIAL Goodridge Functional imprinting of bone marrow progenitors

dependent cytotoxic processes [16], but T cells in the lung airways may have reduced cytolytic function [17, 18]. It has been speculated that this reduced cytotoxic functionality may be a mechanism for reducing excessive pathology in a vital, yet delicate, organ. Perhaps a compromise between maintaining local cellmediated protection against pathogens and the need for preserving lung function may be related to the gradual waning of TRM numbers in the lung. The investigators have raised several exciting questions with respect to the establishment, regulation of longevity, and the protective role of memory T cells in the lung. Local TRM cells promote rapid viral control at the point of viral exposure. Although the gradual disappearance of this protective population diminishes their potential for longterm protection against future infections, additional work may address whether the longevity of this memory population can be enhanced. Additionally, as TRM are critical players in rapid pathogen clearance against heterosubtypic challenges, vaccines may be designed that optimize their generation. An improved understanding of the contribution of TRM to protection during heterosubtypic viral challenges has the potential to advance our application of this new knowledge to the fight against respiratory infections.

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Liang, S., Mozdzanowska, K., Palladino, G., Gerhard, W. (1994) Heterosubtypic immunity to influenza type A virus in mice. Effector mechanisms and their longevity. J. Immunol. 152, 1653–1661. Mueller, S. N., Gebhardt, T., Carbone, F. R., Heath, W. R. (2013) Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 31, 137–161. Gebhardt, T., Wakim, L. M., Eidsmo, L., Reading, P. C., Heath, W. R., Carbone, F. R. (2009) Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 10, 524 –530. Jiang, X., Clark, R. A., Liu, L., Wagers, A. J., Fuhlbrigge, R. C., Kupper, T. S. (2012) Skin infection generates non-migratory memory CD8⫹ TRM cells providing global skin immunity. Nature 483, 227–231. Teijaro, J. R., Turner, D., Pham, Q., Wherry, E. J., Lefrancois, L., Farber, D. L. (2011) Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J. Immunol. 187, 5510 –5514. Schenkel, J. M., Fraser, K. A., Vezys, V., Masopust, D. (2013) Sensing and alarm function of resident memory CD8⫹ T cells. Nat. Immunol. 14, 509 –513. Wu, T., Hu, Y., Lee, Y. T., Bouchard, K. R., Benechet, A., Khanna, K., Cauley, L. S. (2014) Lung-resident memory CD8 T cells (TRM) are indispensable for optimal crossprotection against pulmonary virus infection. J. Leukoc. Biol. 95, 215–224. Masopust, D., Vezys, V., Marzo, A. L., Lefrancois, L. (2001) Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417. Casey, K. A., Fraser, K. A., Schenkel, J. M., Moran, A., Abt, M. C., Beura, L. K., Lucas, P. J., Artis, D., Wherry, E. J., Hogquist, K., Vezys, V., Masopust, D. (2012) Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J. Immunol. 188, 4866 –4875. Schön, M. P., Arya, A., Murphy, E. A., Adams, C. M., Strauch, U. G., Agace, W. W., Marsal, J., Donohue, J. P., Her, H., Deier, D. R., Olson, S., Lefrancois, L., Brenner,

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M. B., Grusby, M. J., Parker, C. M. (1999) Mucosal T lymphocyte numbers are selectively reduced in integrin ␣ E (CD103)-deficient mice. J. Immunol. 162, 6641–6649. Koyama, S. Y., Podolsky, D. K. (1989) Differential expression of transforming growth factors ␣ and ␤ in rat intestinal epithelial cells. J. Clin. Invest. 83, 1768 –1773. Jelley-Gibbs, D. M., Brown, D. M., Dibble, J. P., Haynes, L., Eaton, S. M., Swain, S. L. (2005) Unexpected prolonged presentation of influenza antigens promotes CD4 T cell memory generation. J. Exp. Med. 202, 697– 706. Zammit, D. J., Turner, D. L., Klonowski, K. D., Lefrançois, L., Cauley, L. S. (2006) Residual antigen presentation after influenza virus infection affects CD8 T cell activation and migration. Immunity 24, 439 –449. Lee, Y. T., Suarez-Ramirez, J. E., Wu, T., Redman, J. M., Bouchard, K., Hadley, G. A., Cauley, L. S. (2011) Environmental and antigen receptor-derived signals support sustained surveillance of the lungs by pathogen-specific cytotoxic T lymphocytes. J. Virol. 85, 4085–4094. Strutt, T. M., McKinstry, K. K., Dibble, J. P., Winchell, C., Kuang, Y., Curtis, J. D., Huston, G., Dutton, R. W., Swain, S. L. (2010) Memory CD4⫹ T cells induce innate responses independently of pathogen. Nat. Med. 16, 558 –564. Topham, D. J., Tripp, R. A., Doherty, P. C. (1997) CD8⫹ T cells clear influenza virus by perforin or Fas-dependent processes. J. Immunol. 159, 5197–5200. Vallbracht, S., Unsöld, H., Ehl, S. (2006) Functional impairment of cytotoxic T cells in the lung airways following respiratory virus infections. Eur. J. Immunol. 36, 1434 – 1442. Kohlmeier, J. E., Cookenham, T., Roberts, A. D., Miller, S. C., Woodland, D. L. (2010) Type I interferons regulate cytolytic activity of memory CD8⫹ T cells in the lung airways during respiratory virus challenge. Immunity 33, 96 –105.

KEY WORDS: resident memory 䡠 TRM 䡠 heterosubtypic immunity 䡠 influenza A

Editorial: Bone marrow progenitors share their experiences with their offspring By Helen S. Goodridge1 Regenerative Medicine Institute and Research Division of Immunology, Cedars-Sinai Medical Center, Los Angeles, California, USA RECEIVED AUGUST 27, 2013; REVISED SEPTEMBER 20, 2013; ACCEPTED SEPTEMBER 16, 2013. DOI: 10.1189/jlb.0813464

‹ SEE CORRESPONDING ARTICLE ON PAGE 225

O

ne of the key differences between the innate and adaptive immune responses is the ability of the adaptive immune system to

Abbreviations: HSC⫽hematopoietic stem cell, HSPC⫽hematopoietic stem and progenitor cell

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establish long-term immune memory via the maintenance of antigen-specific lymphocyte populations. Attempts have been made to draw parallels between this mechanism and demonstrations that the function of innate immune cells, such as macrophages, DCs, and NK cells, is impacted by prior encoun-

ters that prime or tolerize subsequent responses [1, 2]. However, such innate immune cell training effects, even if

1. Correspondence: Regenerative Medicine Institute and Research Division of Immunology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA. E-mail: [email protected]

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they are maintained by epigenetic mechanisms, are limited to the lifespan of the exposed cells. Over the past 3 years, Dr. Prue Hart and colleagues at the Telethon Institute for Child Health Research in Perth, Australia, have demonstrated a potentially longer-lasting form of innate “memory” in a series of papers examining the effects of UV radiation and inflammatory mediators on DC function. In previous studies, they demonstrated that bone marrow progenitors from mice exposed to UV radiation or the inflammatory mediator PGE2 produce DCs that are defective in their ability to prime T cell responses [3, 4]. In their latest studies— one in the current issue of the Journal of Leukocyte Biology [5] and the other in a recent issue of the Journal of Immunology [6]— they now demonstrate that the effects of UV irradiation and PGE2 exposure can be transferred by bone marrow transplantation to naive recipient mice and are thus imprinted in HSPCs. UV irradiation can have local and systemic immunosuppressive effects on the ability of DCs to prime T cell responses. Hart and colleagues [3] showed previously that DCs generated in vitro from bone marrow progenitors, isolated from mice that had previously been exposed to UV radiation (localized to the dorsal skin), had a reduced ability to prime T cell responses upon adoptive transfer into naive recipient mice (contact hypersensitivity model). Indomethacin treatment before UV irradiation inhibited this effect, indicating a role for prostanoids produced in response to the UV irradiation, and indeed, DCs derived from bone marrow isolated from PGE2-treated mice were similarly less efficient at priming T cell responses than DCs derived from the bone marrow of control mice. The authors subsequently showed that the DCs that differentiated from the bone marrow of UV-irradiated mice could also suppress the recall response in mice previously sensitized to antigen [7]. In their most recent studies, Hart and colleagues [5, 6] sought to determine whether peripheral DCs newly generated by bone marrow progenitors after UV/ PGE2 exposure contribute to the sustained systemic immunosuppression, which can even affect the progeny of mice exposed to UV radiation during 202 Journal of Leukocyte Biology

pregnancy. To address this, they made chimeric mice by transplanting bone marrow cells from UV/PGE2-exposed mice into bone marrow-ablated, naive recipient mice (Fig. 1A). They found no differences in hematopoietic reconstitution using bone marrow from treated or untreated mice, and DC and T and B cell numbers in the LNs were normal by 16 weeks post-transplant [5, 6]. At this timepoint, the investigators assessed the immune function of the reconstituted mice. They found that contact hypersensitivity responses were reduced in the UV chimeras and the PGE2 chimeras [5, 6] and that allergic airway disease was also reduced in the PGE2 chimeras [5]. Strikingly, in the PGE2 study, they even showed defective contact hypersensitivity responses following serial transplantation of bone marrow from reconstituted mice into secondary recipients [5]. This indicates an effect that can be transmitted via HSCs. In vitro T cell stimulation demonstrated that T cells from the UV-chimeric mice were not defective, and analysis of the UV-chimera DCs showed normal surface expression of MHC II and costimulatory molecules (CD40, CD80, CD86) [6]. However, adoptive transfer of DCs from UV and PGE2 chimeras into naive recipients confirmed their reduced ability to prime T cell responses [5, 6]. Further evaluation of the UV- and the PGE2-chimeric mice demonstrated a failure of antigen-loaded DCs to migrate to draining LNs (Fig. 1) [5, 6]. The reason for this defect is not yet known, but the authors have demonstrated that the defects are cell-intrinsic. As they also showed recently that UV irradiation does not affect in vitro antigen uptake and T cell activation by DCs [7], it seems likely that DC migration is prevented, perhaps as a result of lower basal levels of adhesion molecules and/or chemokine receptors or a failure to up-regulate these migratory molecules following DC activation. The authors have not yet explored this possibility, although they have shown that DCs derived from the bone marrow of UV-irradiated mice express normal surface levels of the lymphoid-homing receptor CCR7 [7]. Consistent with a migratory defect, the authors also observed reduced alum-induced macrophage and neutrophil recruitment to the peritoneum in the PGE2-chimeric mice [5]. Volume 95, February 2014

The demonstrated, functional impact of UV/PGE2 exposure on the progeny of affected bone marrow progenitors produced long after removal of the original stimulus requires: (1) maintenance of the effect in the bone marrow progenitors and (2) transmission of the effect through differentiation, including multiple cell divisions. Epigenetic modifications to the DNA and/or histones often control gene expression when cells differentiate and have been shown to underlie the tolerizing/training effects of microbial stimuli on terminally differentiated myeloid cells [1, 2]. Long-term gene silencing can be maintained by genomic imprinting, which is mediated by methylation [8]. In their recent paper in the Journal of Immunology, Hart and colleagues [6] demonstrated that administration of an inhibitor of DNA methyltransferases restores the ability of DCs derived from the bone marrow of UV-irradiated mice to prime T cell responses in adoptive transfer experiments (Fig. 1B). It is not yet clear whether PGE2 is responsible for this or indeed, whether it is detected directly by the HSPCs, but PGE2 has been shown previously by other investigators to stimulate HSPCs [9] and to induce DNA methylation in tumor cells [10]. In another study, Hart and colleagues [4] found that bone marrow progenitors are similarly affected under other inflammatory conditions, including following i.p. injection of alum. For example, DCs derived in vitro (using GM-CSF or Fmsrelated tyrosine kinase 3 ligand) from bone marrow cells isolated from aluminjected mice were less efficient at priming T cell responses in vivo, an effect that was also mediated by PGE2. Allergic lung disease also had a similar effect. Others have also observed an effect of signals detected by hematopoietic progenitors on the function of macrophages and DCs subsequently produced by them. For example, macrophages and DCs derived in vitro from bone marrow progenitors exposed in vivo to an immunomodulatory nematode protein are less inflammatory than control cells, and the DCs express lower levels of MHC II and the costimulatory molecule CD40 [11]. Similarly, macrophages derived from defined HSPC populations, including HSCs, exposed to a TLR2 agonist are less inflammatory (reduced TNF-␣, IL-6, IL-1␤, and reactive www.jleukbio.org

EDITORIAL Goodridge Functional imprinting of bone marrow progenitors

A UV irradiation dorsal skin

3 days

Contact hypersensitivity model Bone marrow transplant

Reconstitution 16 weeks

Bone marrow chimera

Reduced DC migration and T cell activation Contact hypersensitivity model

Subcutaneous PGE2 delivery 3 days

Bone marrow transplant

Reconstitution 16 weeks

Bone marrow chimera

B

Reduced DC migration and T cell activation

UV irradiation dorsal skin

PGE2

HSPC

* * * *DNA methylation

DC

Differentiation

DC migration to draining lymph nodes

T cell priming

Figure 1. Imprinting of bone marrow progenitors following UV irradiation/PGE2 exposure programs reduced DC function. (A) Hart and colleagues [5– 6] have shown that when bone marrow is collected from mice exposed to UV radiation or PGE2 and transplanted into naive recipient mice, the DCs produced in reconstituted recipient mice are deficient in their ability to prime immune responses. (B) Model of UV/PGE2 imprinting of HSPCs via DNA methylation, which affects the ability of the DCs that they subsequently produce to migrate to LNs and prime T cell responses.

oxygen production) [12]. In these two examples, it is not yet clear how long these effects persist and whether the HSCs remain imprinted following bone marrow transplantation. Interestingly, soluble mediators released by TLR2 agonistexposed progenitors can act in a paracrine manner to influence unexposed progenitors [12]. The current study from Hart and colleagues [5] indicates that PGE2 would be a candidate for future investigation. In conclusion, it appears that inflammatory mediators and microbial compowww.jleukbio.org

nents (via direct detection of microbial components by TLRs on HSPCs or via the action of inflammatory mediators) can imprint HSPCs to influence not just the HSPCs themselves but also the function of their progeny. Future studies will determine whether other functional responses of terminally differentiated myelomonocytic cells are similarly programmed into the HSPCs that produce them and establish the importance of this mechanism in determining the long-term consequences of inflammation. This work also highlights the need to study the functional Volume 95, February 2014

consequences of strategies used to manipulate HSC engraftment, which may also influence the behavior of immune cells in the reconstituted host.

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Foster, S. L., Medzhitov, R. (2009) Genespecific control of the TLR-induced inflammatory response. Clin. Immunol. 130, 7–15. 2. Netea, M. G. (2013) Training innate immunity: the changing concept of immunological memory in innate host defence. Eur. J. Clin. Invest. 43, 881–884. 3. Ng, R. L., Bisley, J. L., Gorman, S., Norval, M., Hart, P. H. (2010) Ultraviolet irradiation of mice reduces the competency of bone

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marrow-derived CD11c⫹ cells via an indomethacin-inhibitable pathway. J. Immunol. 185, 7207–7215. 4. Scott, N. M., Ng, R. L., Strickland, D. H., Bisley, J. L., Bazely, S. A., Gorman, S., Norval, M., Hart, P. H. (2012) Toward homeostasis: regulatory dendritic cells from the bone marrow of mice with inflammation of the airways and peritoneal cavity. Am. J. Pathol. 181, 535–547. 5. Scott, N. M., Ng, R. L., Gorman, S., Norval, M., Waithman, J., Hart, P. H. (2014) Prostaglandin E2 imprints a long-lasting effect on dendritic cell progenitors in the bone marrow. J. Leukoc. Biol. 95, 225–232. 6. Ng, R. L., Scott, N. M., Strickland, D. H., Gorman, S., Grimbaldeston, M. A., Norval, M., Waithman, J., Hart, P. H. (2013) Altered immunity and dendritic cell activity in the periphery of mice after long-term engraftment with bone marrow from ultravio-

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let-irradiated mice. J. Immunol. 190, 5471– 5484. Ng, R. L., Scott, N. M., Bisley, J. L., Lambert, M. J., Gorman, S., Norval, M., Hart, P. H. (2013) Characterisation of regulatory dendritic cells differentiated from the bone marrow of UV-irradiated mice. Immunology 140, 399 – 412. Smith, Z. D., Meissner, A. (2013) DNA methylation: roles in mammalian development. Nat. Rev. Genet. 14, 204 –220. Durand, E. M., Zon, L. I. (2010) Newly emerging roles for prostaglandin E2 regulation of hematopoiesis and hematopoietic stem cell engraftment. Curr. Opin. Hematol. 17, 308 –312. Xia, D., Wang, D., Kim, S. H., Katoh, H., DuBois, R. N. (2012) Prostaglandin E2 promotes intestinal tumor growth via DNA methylation. Nat. Med. 18, 224 –226. Goodridge, H. S., Marshall, F. A., Wilson, E. H., Houston, K. M., Liew, F. Y., Harnett,

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M. M., Harnett, W. (2004) In vivo exposure of murine dendritic cell and macrophage bone marrow progenitors to the phosphorylcholine-containing filarial nematode glycoprotein ES-62 polarizes their differentiation to an anti-inflammatory phenotype. Immunology 113, 491–498. 12. Yanez, A., Hassanzadeh-Kiabi, N., Ng, M. Y., Megias, J., Subramanian, A., Liu, G. Y., Underhill, D. M., Gil, M. L., Goodridge, H. S. (2013) Detection of a TLR2 agonist by hematopoietic stem and progenitor cells impacts the function of the macrophages they produce. Eur. J. Immunol. 43, 2114 –2125.

KEY WORDS: hematopoietic stem and progenitor cells 䡠 DCs 䡠 UV radiation 䡠 PGE2 䡠 imprinting 䡠 DNA methylation

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Editorial: Bone marrow progenitors share their experiences with their offspring.

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