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Prenatal Allospecific NK Cell Tolerance Hinges on Instructive Prenatal Allospecific NK Cell Tolerance Hinges on Instructive Allorecognition through the Activating Receptor during Development This information is current as of September 23, 2021. Amir M. Alhajjat, Beverly S. Strong, Amanda E. Lee, Lucas E. Turner, Ram K. Wadhwani, John R. Ortaldo, Jonathan W. Heusel and Aimen F. Shaaban J Immunol 2015; 195:1506-1516; Prepublished online 1 July 2015; Downloaded from doi: 10.4049/jimmunol.1500463 http://www.jimmunol.org/content/195/4/1506 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2015/07/01/jimmunol.150046 Material 3.DCSupplemental References This article cites 45 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/195/4/1506.full#ref-list-1 Why The JI? Submit online. by guest on September 23, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts 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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Prenatal Allospecific NK Cell Tolerance Hinges on Instructive Allorecognition through the Activating Receptor during Development Amir M. Alhajjat,* Beverly S. Strong,† Amanda E. Lee,† Lucas E. Turner,† Ram K. Wadhwani,† John R. Ortaldo,‡ Jonathan W. Heusel,x,{ and Aimen F. Shaaban† Little is known about how the prenatal interaction between NK cells and alloantigens shapes the developing NK cell repertoire toward tolerance or immunity. Specifically, the effect on NK cell education arising from developmental corecognition of alloantigens by activating and inhibitory receptors with shared specificity is uncharacterized. Using a murine prenatal transplantation model, we examined the manner in which this seemingly conflicting input affects NK cell licensing and repertoire formation in mixed hema- topoietic chimeras. We found that prenatal NK cell tolerance arose from the elimination of phenotypically hostile NK cells that Downloaded from express an allospecific activating receptor without coexpressing any allospecific inhibitory receptors. Importantly, the checkpoint for the system appeared to occur centrally within the bone marrow during the final stage of NK cell maturation and hinged on the instructive recognition of allogeneic ligand by the activating receptor rather than through the inhibitory receptor as classically proposed. Residual nondeleted hostile NK cells expressing only the activating receptor exhibited an immature, anergic phenotype, but retained the capacity to upregulate inhibitory receptor expression in peripheral sites. However, the potential for this adaptive change to occur was lost in developmentally mature chimeras. Collectively, these findings illuminate the intrinsic process in which http://www.jimmunol.org/ developmental allorecognition through the activating receptor regulates the emergence of durable NK cell tolerance and establishes a new paradigm to fundamentally guide future investigations of prenatal NK cell–allospecific education. The Journal of Immu- nology, 2015, 195: 1506–1516. he prenatal exposure to alloantigens is an important feature (11), significant changes occur within the NK cell compartment of immunologic development in eutherian mammals. Both that result in self-tolerance, but maintain otherwise normal T innate and adaptive components of the fetal immune system immunity. Evidence also exists for the instructive influence of have evolved to temper the hazards of alloimmunity or autoimmunity NK cell–activating receptor interactions with environmental with the emergence of prenatal self-tolerance. Since the seminal ligands in altering the phenotype and function of the NK cell by guest on September 23, 2021 work of Owen (1), Burnet et al. (2), and Medawar and colleagues repertoire (12–14). However, animal models in which the target (3), much has been written about the origins of self-tolerance; ligand is ubiquitously expressed throughout development do not however, few studies have examined the mechanisms or signifi- adequately emulate the more complex setting of in utero he- cance of prenatal NK cell tolerance. matopoietic cellular transplantation (IUHCT) or perhaps an Current evidence suggests that NK cell self-tolerance results encounter between a developing fetal NK cell and a maternal from the interaction of inhibitory NK cell receptors with their cell during naturally occurring maternal–fetal cellular traffick- environment, resulting in a mature NK cell repertoire that is fine- ing (15). More specifically, these studies do not permit fine tuned to self-MHC class I expression (4–7). With the gain or loss modulation of the level of ligand exposure to multiple inhibitory of either cognate (8–10) or noncognate MHC class I self-Ags or activating receptors, which is logically the most significant parameter in determining prenatal tolerance or alternatively immunization. *Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, Indeed, we previously confirmed that a minimum level of cir- † IA 52242; Department of Surgery, Cincinnati Children’s Hospital Medical Center culating chimerism is necessary to induce durable NK cell toler- and University of Cincinnati College of Medicine, Cincinnati, OH 45229; ‡Experimental Therapeutics Section, National Cancer Institute, Frederick, MD 21702; xDepartment of ance to prenatally transplanted allogeneic hematopoietic cells (16). Pathology & Immunology, Washington University School of Medicine, St. Louis, MO Recipients with high chimerism levels established and maintained 63110; and {Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110 stable engraftment and exhibited donor-specific NK cell tolerance. Conversely, recipients with low chimerism levels displayed NK ORCID: 0000-0002-9459-107X (A.F.S.). cell–dependent graft rejection. The essence of this quantitative Received for publication February 24, 2015. Accepted for publication June 11, 2015. model for NK cell education is that allospecific tolerance requires This work was supported by National Institutes of Health Grant R01HL103745 and the Children’s Hospital Research Foundation (to A.F.S.). exposure to a critical level of ligand exposure during development— a chimerism threshold. In those experiments, host NK cells from Address correspondence and reprints to Dr. Aimen F. Shaaban, Center for Fetal Cellular and Molecular Therapy, Department of Surgery, Cincinnati Children’s Hos- chimeric mice naturally expressed both activating and inhibitory pital Medical Center, 3333 Burnet Avenue, MLC 11025, Cincinnati, OH 45229-3039. Ly49 receptors that were specific for the donor MHC class I ligands. E-mail address: [email protected] Following preimmune transplantation to an otherwise unmanip- The online version of this article contains supplemental material. ulated allogeneic fetal host, direct trans- recognition of donor cells Abbreviations used in this article: IUHCT, in utero hematopoietic cellular transplan- by activating and inhibitory receptors most likely played a dominant tation; LDMC, light-density mononuclear cell. role in the education of host NK cells, although indirect or even cis Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 recognition by inhibitory receptors resulting from MHC transfer www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500463 The Journal of Immunology 1507 may have had an important role in the education of host NK cells control) and PMA/ionomycin (positive control) wells. Following a 4-h (17–20). It may be speculated that a threshold level of circulating incubation at 37˚C in the presence of brefeldin A (BD Biosciences), the chimerism was critical to each of these mechanisms. In any case, splenocytes were harvested and extracellular staining was performed, as described above, followed by intracellular staining using a BD Cytofix/ current models of NK cell education do not explain how contra- Cytoperm kit (BD Biosciences). Because Abs against NK1.1 were used for dictory activating and inhibitory input signals are reconciled during stimulation, the percentages of NK cells that expressed IFN-g were de- 2 NK cell education to result in rejection or tolerance. In this study, termined by gating on CD3 DX5+ lymphocytes. prenatal allospecific NK cell tolerance was examined in prenatal In vivo BrdU assay chimeras. The present findings illustrate a leading role for the . instructive allorecognition by the activating receptor during Engrafter mice (peripheral blood chimerism 1.8%) and age-matched naive controls were selected at 2, 4, 7, and 10 wk of age. The animals development in determining the mature NK cell repertoire and the were injected with 200 mg BrdU (Sigma-Aldrich) twice daily for 3 d via i.p. functional competence of phenotypically distinct NK cell subsets in injection. On the fourth day, spleen was harvested from both groups and prenatal hematopoietic chimeras. LDMCs
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