Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection.
Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection.
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DOI：
10.3389/fimmu.2021.667393
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发表时间：
2021
影响因子：
7.3
通讯作者：
Allen TM
中科院分区：
文献类型：
--
作者：
Garcia-Beltran WF;Claiborne DT;Maldini CR;Phelps M;Vrbanac V;Karpel ME;Krupp KL;Power KA;Boutwell CL;Balazs AB;Tager AM;Altfeld M;Allen TM
人源化骨髓-肝脏-胸腺（HuBLT）小鼠是一种革命性的小动物模型，促进了人类免疫功能和人类限制性病原体（包括人类免疫缺陷病毒1型（HIV-1））的研究。这些小鼠概括了急性和慢性HIV-1感染的许多方面，但在受到HIV-1攻击时表现出较弱和可变的T细胞反应，阻碍了我们自信地检测HIV-1特异性反应或疫苗效应的能力。为了确定原因，我们全面分析了HuBLT小鼠中T细胞的发育，多样性和功能。我们发现几乎所有的HuBLT都与T细胞良好重构，并且具有完整的TCRβ序列多样性、胸腺发育以及向记忆和效应细胞的分化。然而，存在较差的CD 4+和CD 8 + T细胞对生理刺激的反应性以及与先天性免疫细胞（特别是单核细胞）的重建缺陷相关的降低的TH 1极化。HuBLT小鼠的HIV-1感染表明，具有较高单核细胞重建的小鼠在预测的HLA限制性表位内表现出更高的CD 8 + T细胞应答和HIV-1病毒进化。因此，由于先天免疫细胞的缺乏，HuBLT小鼠对免疫挑战的T细胞应答减弱，未来改善HIV-1免疫应答模型和疫苗研究的努力需要旨在恢复先天免疫重建。
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.
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影响因子：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
影响因子：
25.7
作者：
Hedegaard DL;Tully DC;Rowe IA;Reynolds GM;Bean DJ;Hu K;Davis C;Wilhelm A;Ogilvie CB;Power KA;Tarr AW;Kelly D;Allen TM;Balfe P;McKeating JA
通讯作者：
McKeating JA
影响因子：
3.2
作者：
Jangalwe, Sonal;Shultz, Leonard D;Mathew, Anuja;Brehm, Michael A
通讯作者：
Brehm, Michael A
影响因子：
4.6
作者：
Covassin, L.;Jangalwe, S.;Brehm, M. A.
通讯作者：
Brehm, M. A.
影响因子：
6.4
作者：
Deruaz, Maud;Luster, Andrew D.
通讯作者：
Luster, Andrew D.