Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection
Humanized bone marrow-liver-thymus (HuBLT) mice are a revolutionary small-animal model that has facilitated the study of human immune function and human-restricted pathogens, including human immunodeficiency virus type 1 (HIV-1). These mice recapitulate many aspects of acute and chronic HIV-1 infect...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.667393/full |
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| author | Wilfredo F. Garcia-Beltran Daniel T. Claiborne Colby R. Maldini Meredith Phelps Vladimir Vrbanac Marshall E. Karpel Marshall E. Karpel Katharine L. Krupp Karen A. Power Christian L. Boutwell Alejandro B. Balazs Andrew M. Tager Marcus Altfeld Todd M. Allen |
| author_facet | Wilfredo F. Garcia-Beltran Daniel T. Claiborne Colby R. Maldini Meredith Phelps Vladimir Vrbanac Marshall E. Karpel Marshall E. Karpel Katharine L. Krupp Karen A. Power Christian L. Boutwell Alejandro B. Balazs Andrew M. Tager Marcus Altfeld Todd M. Allen |
| author_sort | Wilfredo F. Garcia-Beltran |
| collection | DOAJ |
| description | Humanized bone marrow-liver-thymus (HuBLT) mice are a revolutionary small-animal model that has facilitated the study of human immune function and human-restricted pathogens, including human immunodeficiency virus type 1 (HIV-1). These mice recapitulate many aspects of acute and chronic HIV-1 infection, but exhibit weak and variable T-cell responses when challenged with HIV-1, hindering our ability to confidently detect HIV-1–specific responses or vaccine effects. To identify the cause of this, we comprehensively analyzed T-cell development, diversity, and function in HuBLT mice. We found that virtually all HuBLT were well-reconstituted with T cells and had intact TCRβ sequence diversity, thymic development, and differentiation to memory and effector cells. However, there was poor CD4+ and CD8+ T-cell responsiveness to physiologic stimuli and decreased TH1 polarization that correlated with deficient reconstitution of innate immune cells, in particular monocytes. HIV-1 infection of HuBLT mice showed that mice with higher monocyte reconstitution exhibited greater CD8+ T cells responses and HIV-1 viral evolution within predicted HLA-restricted epitopes. Thus, T-cell responses to immune challenges are blunted in HuBLT mice due to a deficiency of innate immune cells, and future efforts to improve the model for HIV-1 immune response and vaccine studies need to be aimed at restoring innate immune reconstitution. |
| first_indexed | 2024-12-21T10:45:03Z |
| format | Article |
| id | doaj.art-e6c1b3fbd7f14cf4a30a0e8d524ed2d0 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-21T10:45:03Z |
| publishDate | 2021-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e6c1b3fbd7f14cf4a30a0e8d524ed2d02022-12-21T19:06:50ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-05-011210.3389/fimmu.2021.667393667393Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 InfectionWilfredo F. Garcia-Beltran0Daniel T. Claiborne1Colby R. Maldini2Meredith Phelps3Vladimir Vrbanac4Marshall E. Karpel5Marshall E. Karpel6Katharine L. Krupp7Karen A. Power8Christian L. Boutwell9Alejandro B. Balazs10Andrew M. Tager11Marcus Altfeld12Todd M. Allen13Department of Pathology, Massachusetts General Hospital, Boston, MA, United StatesRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Cambridge, MA, United StatesRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Cambridge, MA, United StatesRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Cambridge, MA, United StatesHuman Immune System Mouse Program, Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United StatesRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Cambridge, MA, United StatesDivision of Medical Sciences, Harvard University, Boston, MA, United StatesRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Cambridge, MA, United StatesRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Cambridge, MA, United StatesRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Cambridge, MA, United StatesRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Cambridge, MA, United StatesCenter for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, United StatesLeibniz Institute for Experimental Virology, Hamburg, GermanyRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Cambridge, MA, United StatesHumanized bone marrow-liver-thymus (HuBLT) mice are a revolutionary small-animal model that has facilitated the study of human immune function and human-restricted pathogens, including human immunodeficiency virus type 1 (HIV-1). These mice recapitulate many aspects of acute and chronic HIV-1 infection, but exhibit weak and variable T-cell responses when challenged with HIV-1, hindering our ability to confidently detect HIV-1–specific responses or vaccine effects. To identify the cause of this, we comprehensively analyzed T-cell development, diversity, and function in HuBLT mice. We found that virtually all HuBLT were well-reconstituted with T cells and had intact TCRβ sequence diversity, thymic development, and differentiation to memory and effector cells. However, there was poor CD4+ and CD8+ T-cell responsiveness to physiologic stimuli and decreased TH1 polarization that correlated with deficient reconstitution of innate immune cells, in particular monocytes. HIV-1 infection of HuBLT mice showed that mice with higher monocyte reconstitution exhibited greater CD8+ T cells responses and HIV-1 viral evolution within predicted HLA-restricted epitopes. Thus, T-cell responses to immune challenges are blunted in HuBLT mice due to a deficiency of innate immune cells, and future efforts to improve the model for HIV-1 immune response and vaccine studies need to be aimed at restoring innate immune reconstitution.https://www.frontiersin.org/articles/10.3389/fimmu.2021.667393/fullinnate immunityT cellsHIV-1HuBLTBLThumanized mice |
| spellingShingle | Wilfredo F. Garcia-Beltran Daniel T. Claiborne Colby R. Maldini Meredith Phelps Vladimir Vrbanac Marshall E. Karpel Marshall E. Karpel Katharine L. Krupp Karen A. Power Christian L. Boutwell Alejandro B. Balazs Andrew M. Tager Marcus Altfeld Todd M. Allen Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection Frontiers in Immunology innate immunity T cells HIV-1 HuBLT BLT humanized mice |
| title | Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection |
| title_full | Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection |
| title_fullStr | Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection |
| title_full_unstemmed | Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection |
| title_short | Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection |
| title_sort | innate immune reconstitution in humanized bone marrow liver thymus hublt mice governs adaptive cellular immune function and responses to hiv 1 infection |
| topic | innate immunity T cells HIV-1 HuBLT BLT humanized mice |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.667393/full |
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