A major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. However, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. Here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implant. We demonstrate that emerging and clinically relevant human pathogens such as Middle East respiratory syndrome coronavirus, Zika virus, respiratory syncytial virus and cytomegalovirus replicate in vivo in these lung implants. When incorporated into bone marrow/liver/thymus humanized mice, lung implants are repopulated with autologous human hematopoietic cells. We show robust antigen-specific humoral and T-cell responses following cytomegalovirus infection that control virus replication. Lung-only mice and bone marrow/liver/thymus-lung humanized mice substantially increase the number of human pathogens that can be studied in vivo, facilitating the in vivo testing of therapeutics.
Subscribe to Journal
Get full journal access for 1 year
only $20.83 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data generated are available from corresponding authors on reasonable request.
Cockrell, A. S. et al. A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nat. Microbiol. 2, 16226 (2016).
Morrison, T. E. & Diamond, M. S. Animal models of Zika virus infection, pathogenesis, and immunity. J. Virol. 91, e00009–17 (2017).
Safronetz, D., Geisbert, T. W. & Feldmann, H. Animal models for highly pathogenic emerging viruses. Curr. Opin. Virol. 3, 205–209 (2013).
Schmitt, K. et al. Zika viral infection and neutralizing human antibody response in a BLT humanized mouse model. Virology 515, 235–242 (2018).
Crawford, L. B., Streblow, D. N., Hakki, M., Nelson, J. A. & Caposio, P. Humanized mouse models of human cytomegalovirus infection. Curr. Opin. Virol. 13, 86–92 (2015).
Taylor, G. Animal models of respiratory syncytial virus infection. Vaccine 35, 469–480 (2017).
Gupta, U. D. & Katoch, V. M. Animal models of tuberculosis. Tuberculosis (Edinb.) 85, 277–293 (2005).
Fonseca, K. L., Rodrigues, P. N. S., Olsson, I. A. S. & Saraiva, M. Experimental study of tuberculosis: from animal models to complex cell systems and organoids. PLoS Pathog. 13, e1006421 (2017).
Pickles, R. J. & DeVincenzo, J. P. Respiratory syncytial virus (RSV) and its propensity for causing bronchiolitis. J. Pathol. 235, 266–276 (2015).
Perlman, R. L. Mouse models of human disease: an evolutionary perspective. Evol. Med. Public Health 2016, 170–176 (2016).
Shultz, L. D., Brehm, M. A., Garcia-Martinez, J. V. & Greiner, D. L. Humanized mice for immune system investigation: progress, promise and challenges. Nat. Rev. Immunol. 12, 786–798 (2012).
Garcia, J. V. Humanized mice for HIV and AIDS research. Curr. Opin. Virol. 19, 56–64 (2016).
Wahl, A. et al. A cluster of virus-encoded microRNAs accelerates acute systemic Epstein–Barr virus infection but does not significantly enhance virus-induced oncogenesis in vivo. J. Virol. 87, 5437–5446 (2013).
Melkus, M. W. et al. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat. Med. 12, 1316–1322 (2006).
Islas-Ohlmayer, M. et al. Experimental infection of NOD/SCID mice reconstituted with human CD34+ cells with Epstein–Barr virus. J. Virol. 78, 13891–13900 (2004).
Bente, D. A., Melkus, M. W., Garcia, J. V. & Rico-Hesse, R. Dengue fever in humanized NOD/SCID mice. J. Virol. 79, 13797–13799 (2005).
Smith, M. S. et al. Granulocyte-colony stimulating factor reactivates human cytomegalovirus in a latently infected humanized mouse model. Cell Host Microbe 8, 284–291 (2010).
Crawford, L. B. et al. Human cytomegalovirus induces cellular and humoral virus-specific immune responses in humanized BLT mice. Sci. Rep. 7, 937 (2017).
Wang, L. X. et al. Humanized-BLT mouse model of Kaposi’s sarcoma-associated herpesvirus infection. Proc. Natl Acad. Sci. USA 111, 3146–3151 (2014).
Cockrell, A. S. et al. Mouse dipeptidyl peptidase 4 is not a functional receptor for Middle East respiratory syndrome coronavirus infection. J. Virol. 88, 5195–5199 (2014).
Coleman, C. M., Matthews, K. L., Goicochea, L. & Frieman, M. B. Wild-type and innate immune-deficient mice are not susceptible to the Middle East respiratory syndrome coronavirus. J. Gen. Virol. 95, 408–412 (2014).
Martinez-Torres, F., Nochi, T., Wahl, A., Garcia, J. V. & Denton, P. W. Hypogammaglobulinemia in BLT humanized mice—an animal model of primary antibody deficiency. PloS ONE 9, e108663 (2014).
Nochi, T., Denton, P. W., Wahl, A. & Garcia, J. V. Cryptopatches are essential for the development of human GALT. Cell Rep. 3, 1874–1884 (2013).
Dudek, T. E. et al. Rapid evolution of HIV-1 to functional CD8(+) T cell responses in humanized BLT mice. Sci. Transl. Med. 4, 143ra198 (2012).
Brainard, D. M. et al. Induction of robust cellular and humoral virus-specific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice. J. Virol. 83, 7305–7321 (2009).
Zhou, J., Chu, H., Chan, J. F. & Yuen, K. Y. Middle East respiratory syndrome coronavirus infection: virus-host cell interactions and implications on pathogenesis. Virol. J. 12, 218 (2015).
Frumence, E. et al. The South Pacific epidemic strain of Zika virus replicates efficiently in human epithelial A549 cells leading to IFN-β production and apoptosis induction. Virology 493, 217–226 (2016).
Liu, S., DeLalio, L. J., Isakson, B. E. & Wang, T. T. AXL-mediated productive infection of human endothelial cells by Zika virus. Circ. Res. 119, 1183–1189 (2016).
Hamel, R. et al. Biology of Zika virus infection in human skin cells. J. Virol. 89, 8880–8896 (2015).
Franks, T. J. et al. Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function. Proc. Am. Thorac. Soc. 5, 763–766 (2008).
Sousa, A. Q. et al. Postmortem findings for 7 neonates with congenital Zika virus infection. Emerg. Infect. Dis. 23, 1164–1167 (2017).
Cunha, B. A. Cytomegalovirus pneumonia: community-acquired pneumonia in immunocompetent hosts. Infect. Dis. Clin. North Am. 24, 147–158 (2010).
Gordon, C. L. et al. Tissue reservoirs of antiviral T cell immunity in persistent human CMV infection. J. Exp. Med. 214, 651–667 (2017).
Lyon, S. M. & Rossman, M. D. Pulmonary tuberculosis. Microbiol. Spectr. 5, 1–13 (2017).
Gessner, R. et al. High-resolution, high-contrast ultrasound imaging using a prototype dual-frequency transducer: in vitro and in vivo studies. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57, 1772–1781 (2010).
Gessner, R. C., Frederick, C. B., Foster, F. S. & Dayton, P. A. Acoustic angiography: a new imaging modality for assessing microvasculature architecture. International J. Biomed. Imaging 2013, 936593 (2013).
Davis, L. S. et al. Inflammation, immune reactivity, and angiogenesis in a severe combined immunodeficiency model of rheumatoid arthritis. Am. J. Pathol. 160, 357–367 (2002).
Huang, S. Y., Tien, H. F., Su, F. H. & Hsu, S. M. Nonirradiated NOD/SCID-human chimeric animal model for primary human multiple myeloma: a potential in vivo culture system. Am. J. Pathol. 164, 747–756 (2004).
Hou, W. et al. Determination of the cell permissiveness spectrum, mode of RNA replication, and RNA-protein interaction of Zika virus. BMC Infect. Dis. 17, 239 (2017).
Liesman, R. M. et al. RSV-encoded NS2 promotes epithelial cell shedding and distal airway obstruction. J. Clin. Invest. 124, 2219–2233 (2014).
Aherne, W., Bird, T., Court, S. D., Gardner, P. S. & McQuillin, J. Pathological changes in virus infections of the lower respiratory tract in children. J. Clin. Pathol. 23, 7–18 (1970).
Arend, K. C., Ziehr, B., Vincent, H. A. & Moorman, N. J. Multiple transcripts encode full-length human cytomegalovirus IE1 and IE2 proteins during lytic infection. J. Virol. 90, 8855–8865 (2016).
Azevedo, L. S. et al. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paulo) 70, 515–523 (2015).
Sathaliyawala, T. et al. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 38, 187–197 (2013).
Pitt, E. A. et al. The D-form of a novel heparan binding peptide decreases cytomegalovirus infection in vivo and in vitro. Antiviral Res. 135, 15–23 (2016).
Sinzger, C. et al. Cloning and sequencing of a highly productive, endotheliotropic virus strain derived from human cytomegalovirus TB40/E. J. Gen. Virol. 89, 359–368 (2008).
Ostermann, E., Spohn, M., Indenbirken, D. & Brune, W. Complete genome sequence of a human cytomegalovirus strain AD169 bacterial artificial chromosome clone. Genome Announc. 4, 1–2 (2016).
Wang, D. & Shenk, T. Human cytomegalovirus UL131 open reading frame is required for epithelial cell tropism. J. Virol. 79, 10330–10338 (2005).
Munro, S. C. et al. Diagnosis of and screening for cytomegalovirus infection in pregnant women. J. Clin. Microbiol. 43, 4713–4718 (2005).
Gamadia, L. E., Rentenaar, R. J., van Lier, R. A. & ten Berge, I. J. Properties of CD4(+) T cells in human cytomegalovirus infection. Hum. Immunol. 65, 486–492 (2004).
Vaz-Santiago, J. et al. Ex vivo stimulation and expansion of both CD4(+) and CD8(+) T cells from peripheral blood mononuclear cells of human cytomegalovirus-seropositive blood donors by using a soluble recombinant chimeric protein, IE1-pp65. J. Virol. 75, 7840–7847 (2001).
Sinclair, E. et al. CMV antigen-specific CD4+ and CD8+ T cell IFNγ expression and proliferation responses in healthy CMV-seropositive individuals. Viral Immunol. 17, 445–454 (2004).
Gillespie, G. M. et al. Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors. J. Virol. 74, 8140–8150 (2000).
Nastke, M. D. et al. Major contribution of codominant CD8 and CD4 T cell epitopes to the human cytomegalovirus-specific T cell repertoire. Cell. Mol. Life Sci. 62, 77–86 (2005).
Kessing, C. F. et al. In vivo suppression of HIV rebound by didehydro-cortistatin a, a “block-and-lock” strategy for HIV-1 treatment. Cell Rep. 21, 600–611 (2017).
Kovarova, M. et al. A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges. J. Antimicrob. Chemother. 71, 1586–1596 (2016).
Tsai, P. et al. CD19xCD3 DART protein mediates human B-cell depletion in vivo in humanized BLT mice. Mol. Ther. Oncolytics 3, 15024 (2016).
Lilleri, D., Zelini, P., Fornara, C., Comolli, G. & Gerna, G. Inconsistent responses of cytomegalovirus-specific T cells to pp65 and IE-1 versus infected dendritic cells in organ transplant recipients. Am. J. Transplant. 7, 1997–2005 (2007).
Jackson, S. E., Mason, G. M., Okecha, G., Sissons, J. G. & Wills, M. R. Diverse specificities, phenotypes, and antiviral activities of cytomegalovirus-specific CD8+ T cells. J. Virol. 88, 10894–10908 (2014).
Braendstrup, P. et al. Identification and HLA-tetramer-validation of human CD4+ and CD8+ T cell responses against HCMV proteins IE1 and IE2. PloS ONE 9, e94892 (2014).
Khan, N., Cobbold, M., Keenan, R. & Moss, P. A. Comparative analysis of CD8+ T cell responses against human cytomegalovirus proteins pp65 and immediate early 1 shows similarities in precursor frequency, oligoclonality, and phenotype. J. Infect. Dis. 185, 1025–1034 (2002).
Sacre, K. et al. Expansion of human cytomegalovirus (HCMV) immediate-early 1-specific CD8+ T cells and control of HCMV replication after allogeneic stem cell transplantation. J. Virol. 82, 10143–10152 (2008).
Honeycutt, J. B. et al. Macrophages sustain HIV replication in vivo independently of T cells. J. Clin. Invest. 126, 1353–1366 (2016).
Olesen, R. et al. ART influences HIV persistence in the female reproductive tract and cervicovaginal secretions. J. Clin. Invest. 126, 892–904 (2016).
Shelton, S. E. et al. Quantification of microvascular tortuosity during tumor evolution using acoustic angiography. Ultrasound Med. Biol. 41, 1896–1904 (2015).
Honeycutt, J. B. et al. HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy. Nat. Med. 23, 638–643 (2017).
Fulcher, M. L., Gabriel, S., Burns, K. A., Yankaskas, J. R. & Randell, S. H. Well-differentiated human airway epithelial cell cultures. Methods Mol. Med. 107, 183–206 (2005).
Zhang, S. et al. Neutralization mechanism of a highly potent antibody against Zika virus. Nat. Commun. 7, 13679 (2016).
Lanciotti, R. S. et al. Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerg. Infect. Dis. 14, 1232–1239 (2008).
Hallak, L. K., Spillmann, D., Collins, P. L. & Peeples, M. E. Glycosaminoglycan sulfation requirements for respiratory syncytial virus infection. J. Virol. 74, 10508–10513 (2000).
O’Connor, C. M. & Shenk, T. Human cytomegalovirus pUS27 G protein-coupled receptor homologue is required for efficient spread by the extracellular route but not for direct cell-to-cell spread. J. Virol. 85, 3700–3707 (2011).
Wang, D., Bresnahan, W. & Shenk, T. Human cytomegalovirus encodes a highly specific RANTES decoy receptor. Proc. Natl Acad. Sci. USA 101, 16642–16647 (2004).
Ziehr, B., Lenarcic, E., Cecil, C. & Moorman, N. J. The eIF4AIII RNA helicase is a critical determinant of human cytomegalovirus replication. Virology 489, 194–201 (2016).
Goonetilleke, N. et al. Induction of multifunctional human immunodeficiency virus type 1 (HIV-1)-specific T cells capable of proliferation in healthy subjects by using a prime-boost regimen of DNA- and modified vaccinia virus Ankara-vectored vaccines expressing HIV-1 Gag coupled to CD8+ T-cell epitopes. J. Virol. 80, 4717–4728 (2006).
This work was supported by NIH grants no. AI103311 (N.J.M.), no. AI123811 (N.J.M.), no. AI110700 (R.S.B.), no. AI100625 (R.S.B.), no. P30 AI027763 (N.G.), no. AI113736 (R.J.P.), no. T32 HL069768 (I.G.N.), no. AI123010 (A.W.), no. AI111899 (J.V.G.), no. AI140799 (J.V.G.), no. MH108179 (J.V.G.), no. CA189479 (P.A.D.) and no. CA170665 (P.A.D) and the North Carolina University Cancer Research Fund (N.J.M.). This work was also supported by the UNC Center for AIDS Research (CFAR) (grant no. P30 AI050410). We thank K. Arend for the generation of HCMV virus stocks used in these experiments. We thank P. Collins and M. Peeples for recombinant RSV expressing GFP and C. O’Connor for recombinant HCMV TB40/E expressing luciferase. We thank G. Clutton for input on the analysis of antigen-specific T-cell responses. The authors thank members of the Garcia laboratory for technical assistance. We thank technicians at the UNC Animal Histopathology Core, The Marsico Lung Institute Tissue and Procurement Core, and the Department of Comparative Medicine. We also thank J. Schmitz and technicians at the UNC Clinical Microbiology/Immunology Laboratories. We thank J. Nelson and technicians at the UNC CFAR Virology Core Laboratory and K. Mollan at the UNC CFAR Biostatistics Core. The authors thank M.T. Heise, L.J. Picker and J.P. Ting for manuscript advice and helpful discussions.
P.A.D. is an inventor of the acoustic angiography imaging technique, and a cofounder of SonoVol, Inc., a company that has licensed this patent.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Integrated supplementary information
Supplementary Figure 1 Histological analysis of the structure and cellular composition of donor matched human lung tissue pre- and post-implantation.
The structure and cellular composition of human lung tissue pre-implantation (n=2 analyzed) and donor matched LoM lung implant harvested 2 months post-implantation (n=4 analyzed) were analyzed by (a) H&E and (b) immunofluorescent staining. In b, co-staining was performed for epithelial cells (cytokeratin 19, magenta) and cilia (alpha-acetylated tubulin, green) or club cells (CC10, green). Arrows show cuboidal cells lining alveoli. In a, scale bars are 100 µm (left panel) and 200 µm (right panel). In b, scale bars are 200 µm (left panels) and 100 µm (right panels).
Supplementary Figure 2 Presence of mouse cells in the human lung implants of LoM and NSG mouse lung.
Immunohistochemical staining for murine epithelial cells, endothelial cells, hematopoietic cells in LoM human lung implants (n=3 analyzed, top panels) and the mouse lung (n=1 analyzed, bottom panels). Images: 10X, scale bars: 100 µm, positive cells: brown. m, mouse.
Supplementary Figure 3 Presence of human immune cells in human lung tissue pre- and post-implantation.
Immunohistochemical staining for human hematopoietic (hCD45) cells including macrophages (hCD68), dendritic cells (hCD11c), B cells (hCD20) and T cells (hCD3) in human donor matched lung tissue pre-implantation (n=1 analyzed, left panels) and two months post-implantation (n=1 analyzed, right panels). Images: 10X, scale bars: 100 µm, positive cells: brown.
Supplementary Figure 4 In vivo gene expression profile of HCMV-infected LoM is consistent with lytic replication.
Total RNA was extracted from human lung implants harvested from HCMV TB40/E infected LoM 14 days post exposure (n=2 TB40/E infected implants). Double stranded cDNA ((ds)cDNA) was generated from ribosomal RNA (rRNA) depleted total RNA. HCMV (ds)cDNA was enriched with custom designed biotinylated probes spanning both strands of the entire HCMV genome and sequenced using next generation sequencing. High quality reads were aligned to the HCMV genome, and viral expression was quantified in read per kilobase per million (rpkm). Values show read counts per gene normalized to gene length read (rpkm).
Supplementary Figure 5 Reconstitution of the peripheral blood of BLT-L mice with human innate and adaptive immune cells.
Levels of (a) human hematopoietic cells (hCD45) including (b) human myeloid cells (hCD33), B cells (hCD19) and T cells (hCD3) as well as the (c) levels of CD4+ (hCD4) and CD8+ (hCD8) T cells and (d) ratio of human CD4:CD8 T cells in the peripheral blood of BLT-L mice (n=11, filled circles). Horizontal lines represent mean ± s.e.m.
Supplementary Figure 6 Levels of human immune cells in the human lung implants and mouse lung of BLT-L mice.
Levels of (a) human hematopoietic cells (hCD45) including (b) human myeloid cells (hCD33), B cells (hCD19) and T cells (hCD3) in the human lung implants (circles; hCD45, hCD33, and hCD3 n=18, hCD19 n=15) and mouse lung (squares, n=11) of BLT-L mice. (c) Levels of CD4+ (hCD4) and CD8+ (hCD8) T cells and (d) ratio of human CD4:CD8 T cells in the human lung implants (circles, n=15) and mouse lungs (squares, n=11) of BLT-L mice. (e) Human CD4+ and CD8+ T cell activation (CD38+HLA-DR+) levels in the human lung implant (circles, n=7) and mouse lung (squares, n=4) of BLT-L mice. Horizontal lines represent mean ± s.e.m. Human immune cell levels in the human lung implants and mouse lung were compared with a two-tailed Mann-Whitney test.
(a-c) The memory phenotype of human T cells in the human lung implants of BLT-L mice (n=4 BLT-L mice, one lung implant per animal). (a) Percent of CD4+ (filled circles) and CD8+ (filled squares) human T cells expressing a memory phenotype (CD45RO+). (b) Percent of memory (CD45RO+) CD4+ (circles) and CD8+ (squares) human T cells expressing an effector memory (Tem, CCR7neg, closed symbols) or central memory (Tcm, CCR7+, open symbols) phenotype. (c) Percent of memory (CD45RO+) CD4+ (filled circles) and CD8+ (filled squares) T cells that are tissue-resident (TRM, CD69+). (d) Flow cytometry gating scheme. Regions identify the following human cell populations: RI (live cells), RII (human hematopoietic cells), RIII (T cells), RIV (CD8+ T cells), RV (CD4+ T cells), RVI (memory CD8+ T cells), RVII (CD8+ Tem), RVIII (CD8+ Tcm), RIX (CD8+ TRM), RX (memory CD4+ T cells), RXI (CD4+ Tem), RXII (CD4+ Tcm) and RXIII (CD4+ TRM). In a-c, horizontal lines represent mean ± s.e.m. (e) Human hematopoietic (hCD45) cells including dendritic cells (hCD11c), macrophages (hCD68), B cells (hCD20) and T cells (hCD3, hCD4 and hCD8) in lymphoid (spleen and lymph nodes) and non-lymphoid (liver and mouse lung) of BLT-L mice by immunohistochemical staining (positive cells: brown). Images shown are at 20X magnification and represent three BLT-L mice (scale bars: 100 µm).
Supplementary Figure 8 Increased plasma human cytokine and chemokine levels in BLT-L mice following HCMV exposure.
Levels of human GM-CSF IFN-γ, IL-6, IL-8, MDC, IP-10, GRO and MCP-1 in the PB plasma of BLT-L mice (n=10 mice, filled circles) pre and 4 days after HCMV TB40/E inoculation. A value of 3.2 pg/ml was graphed for measurements below the limit of detection of the assay (3.2 pg/ml, shown with a dashed line). Human cytokine and chemokine levels pre and post HCMV inoculation were compared with a two-tailed Wilcoxon matched-pairs signed rank test.
(a) HCMV-DNA levels in LoM human lung implants at 4, 7, 14, 21 and 28 days post AD169 exposure (day 4: n=3 implants, days 7, 14, 21 and 28: n=4 implants, filled squares). Horizontal lines represent mean ± s.e.m. (b) HCMV immediate early (IE), early (E) and late (L) proteins in the human lung implant of an AD169-infected LoM 21 days post-exposure (n=1 lung implant analyzed, positive cells: brown). Images shown are at 40X magnification (scale bars: 50 µm). Positive cells in the bottom panel are indicated with black arrows.
Heat-inactivated plasma from naïve (n=1, open blue circles) and repeatedly HCMV TB40/E exposed BLT-L mice (n=6, filled symbols) was incubated with HCMV TB40/E expressing RFP for 1 h prior to the addition of virus to epithelial cells (ARPE-19). Epithelial cells were incubated at 37 °C with the virus/plasma mixture for 2 h at which time the virus/plasma mixture was removed and fresh media added. Shown is the number of HCMV TB40/E-RFP+ epithelial cells 72 h post-infection in quadruplicate wells. Horizontal lines represent mean ± s.e.m. The percent reduction in TB40/E RFP+ cells compared to wells infected with HCMV pre-treated with naïve control plasma is shown in the table.
Supplementary Figure 11 Gating strategies for the identification of HCMV-specific human T cell responses in BLT-L mice by intracellular cytokine staining (ICS) and pentamer staining.
Representative flow cytometry plots indicating the gating used to detect (a) human CD8+ T cells expressing IFN-γ and CD107a and (b) human CD4+ T cells expressing IFN-γ and TNFα by ICS. (c) Representative flow cytometry plots indicating the gating strategy used to detect HLA class1a-restricted HCMV-specific human CD8+ T cells by pentamer staining.
Supplementary Figs. 1–11 and Supplementary Tables 1–10
Three-dimensional rendering of vascularization (red) of a human lung implant (blue).
About this article
Nature Biotechnology (2019)