Impact of CMV Infection on Natural Killer Cell Clonal Repertoire in CMV-Naïve Rhesus Macaques
Recent functional, gene expression, and epigenetic studies have suggested the presence of a subset of mature natural killer (NK) cells responsible for maintaining NK cell memory. The lack of endogenous clonal markers in NK cells impedes understanding the genesis of these cell populations. In humans,...
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Frontiers Media S.A.
2019-10-01
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Series: | Frontiers in Immunology |
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Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02381/full |
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doaj-cd238f4bc5384c8ca993c13401ddbd33 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lauren L. Truitt Di Yang Di Yang Diego A. Espinoza Diego A. Espinoza Xing Fan Daniel R. Ram Matilda J. Moström Dollnovan Tran Lesli M. Sprehe R. Keith Reeves R. Keith Reeves Robert E. Donahue Amitinder Kaur Cynthia E. Dunbar Chuanfeng Wu |
spellingShingle |
Lauren L. Truitt Di Yang Di Yang Diego A. Espinoza Diego A. Espinoza Xing Fan Daniel R. Ram Matilda J. Moström Dollnovan Tran Lesli M. Sprehe R. Keith Reeves R. Keith Reeves Robert E. Donahue Amitinder Kaur Cynthia E. Dunbar Chuanfeng Wu Impact of CMV Infection on Natural Killer Cell Clonal Repertoire in CMV-Naïve Rhesus Macaques Frontiers in Immunology NK cells cytomegalovirus adaptive memory barcoding clonality |
author_facet |
Lauren L. Truitt Di Yang Di Yang Diego A. Espinoza Diego A. Espinoza Xing Fan Daniel R. Ram Matilda J. Moström Dollnovan Tran Lesli M. Sprehe R. Keith Reeves R. Keith Reeves Robert E. Donahue Amitinder Kaur Cynthia E. Dunbar Chuanfeng Wu |
author_sort |
Lauren L. Truitt |
title |
Impact of CMV Infection on Natural Killer Cell Clonal Repertoire in CMV-Naïve Rhesus Macaques |
title_short |
Impact of CMV Infection on Natural Killer Cell Clonal Repertoire in CMV-Naïve Rhesus Macaques |
title_full |
Impact of CMV Infection on Natural Killer Cell Clonal Repertoire in CMV-Naïve Rhesus Macaques |
title_fullStr |
Impact of CMV Infection on Natural Killer Cell Clonal Repertoire in CMV-Naïve Rhesus Macaques |
title_full_unstemmed |
Impact of CMV Infection on Natural Killer Cell Clonal Repertoire in CMV-Naïve Rhesus Macaques |
title_sort |
impact of cmv infection on natural killer cell clonal repertoire in cmv-naïve rhesus macaques |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2019-10-01 |
description |
Recent functional, gene expression, and epigenetic studies have suggested the presence of a subset of mature natural killer (NK) cells responsible for maintaining NK cell memory. The lack of endogenous clonal markers in NK cells impedes understanding the genesis of these cell populations. In humans, primates, and mice, this phenotype and memory or adaptive functions have been strongly linked to cytomegalovirus or related herpes virus infections. We have used transplantation of lentivirally-barcoded autologous hematopoietic stem and progenitor cells (HSPC) to track clonal hematopoiesis in rhesus macaques and previously reported striking oligoclonal expansions of NK-biased barcoded clones within the CD56−CD16+ NK cell subpopulation, clonally distinct from ongoing output of myeloid, B cell, T cell, and CD56+16− NK cells from HSPC. These CD56−CD16+ NK cell clones segregate by expression of specific KIR surface receptors, suggesting clonal expansion in reaction to specific environmental stimuli. We have now used this model to investigate the impact of rhesus CMV(RhCMV) infection on NK clonal dynamics. Following transplantation, RhCMVneg rhesus macaques display less dominant and oligoclonal CD16+ NK cells biased clones compared to RhCMVpos animals, however these populations of cells are still clearly present. Upon RhCMV infection, CD16+ NK cells proliferate, followed by appearance of new groups of expanded NK clones and disappearance of clones present prior to RhCMV infection. A second superinfection with RhCMV resulted in rapid viral clearance without major change in the mature NK cell clonal landscape. Our findings suggest that RhCMV is not the sole driver of clonal expansion and peripheral maintenance of mature NK cells; however, infection of macaques with this herpesvirus does result in selective expansion and persistence of specific NK cell clones, providing further information relevant to adaptive NK cells and the development of NK cell therapies. |
topic |
NK cells cytomegalovirus adaptive memory barcoding clonality |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2019.02381/full |
work_keys_str_mv |
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doaj-cd238f4bc5384c8ca993c13401ddbd332020-11-24T21:36:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-10-011010.3389/fimmu.2019.02381488392Impact of CMV Infection on Natural Killer Cell Clonal Repertoire in CMV-Naïve Rhesus MacaquesLauren L. Truitt0Di Yang1Di Yang2Diego A. Espinoza3Diego A. Espinoza4Xing Fan5Daniel R. Ram6Matilda J. Moström7Dollnovan Tran8Lesli M. Sprehe9R. Keith Reeves10R. Keith Reeves11Robert E. Donahue12Amitinder Kaur13Cynthia E. Dunbar14Chuanfeng Wu15Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United StatesTranslational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United StatesInstitute of Hematology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, ChinaTranslational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United StatesPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United StatesTranslational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United StatesCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United StatesTulane National Primate Research Center, Covington, LA, United StatesTulane National Primate Research Center, Covington, LA, United StatesTulane National Primate Research Center, Covington, LA, United StatesCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United StatesRagon Institute of Massachusetts General Hospital, MIT, and Harvard, Cambridge, MA, United StatesTranslational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United StatesTulane National Primate Research Center, Covington, LA, United StatesTranslational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United StatesTranslational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United StatesRecent functional, gene expression, and epigenetic studies have suggested the presence of a subset of mature natural killer (NK) cells responsible for maintaining NK cell memory. The lack of endogenous clonal markers in NK cells impedes understanding the genesis of these cell populations. In humans, primates, and mice, this phenotype and memory or adaptive functions have been strongly linked to cytomegalovirus or related herpes virus infections. We have used transplantation of lentivirally-barcoded autologous hematopoietic stem and progenitor cells (HSPC) to track clonal hematopoiesis in rhesus macaques and previously reported striking oligoclonal expansions of NK-biased barcoded clones within the CD56−CD16+ NK cell subpopulation, clonally distinct from ongoing output of myeloid, B cell, T cell, and CD56+16− NK cells from HSPC. These CD56−CD16+ NK cell clones segregate by expression of specific KIR surface receptors, suggesting clonal expansion in reaction to specific environmental stimuli. We have now used this model to investigate the impact of rhesus CMV(RhCMV) infection on NK clonal dynamics. Following transplantation, RhCMVneg rhesus macaques display less dominant and oligoclonal CD16+ NK cells biased clones compared to RhCMVpos animals, however these populations of cells are still clearly present. Upon RhCMV infection, CD16+ NK cells proliferate, followed by appearance of new groups of expanded NK clones and disappearance of clones present prior to RhCMV infection. A second superinfection with RhCMV resulted in rapid viral clearance without major change in the mature NK cell clonal landscape. Our findings suggest that RhCMV is not the sole driver of clonal expansion and peripheral maintenance of mature NK cells; however, infection of macaques with this herpesvirus does result in selective expansion and persistence of specific NK cell clones, providing further information relevant to adaptive NK cells and the development of NK cell therapies.https://www.frontiersin.org/article/10.3389/fimmu.2019.02381/fullNK cellscytomegalovirusadaptive memorybarcodingclonality |