Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+ T cells and successful immunotherapy against chronic viral liver infection
Abstract
Chronic infection is difficult to overcome because of exhaustion or depletion of cytotoxic effector CD8(+) T cells (cytotoxic T lymphoytes (CTLs)). Here we report that signaling via Toll-like receptors (TLRs) induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (iMATEs: 'intrahepatic myeloid-cell aggregates for T cell population expansion') without causing immunopathology. In the liver, CTL proliferation was restricted to iMATEs that were composed of inflammatory monocyte-derived CD11b(+) cells. Signaling via tumor-necrosis factor (TNF) caused iMATE formation that facilitated costimulation dependent on the receptor OX40 for expansion of the CTL population. The iMATEs arose during acute viral infection but were absent during chronic viral infection, yet they were still induced by TLR signaling. Such hepatic expansion of the CTL population controlled chronic viral infection of the liver after vaccination with DNA. Thus, iMATEs are dynamic structures that overcome regulatory cues that limit the population expansion of CTLs during chronic infection and can be used in new therapeutic vaccination strategies.
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Upon TLR9 stimulation, effector CD8+ T cells can expand in an antigen-independent way.
“Upon TLR9 stimulation, they can expand in an antigen-independent way(104).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [104]
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BackgroundInfluentialAge-dependent hepatic lymphoid organization directs successful immunity to hepatitis B
Publicover, J., Gaggar, A., Nishimura, S. L., Horn, C. M. V., Goodsell, A., Muench, M. O., Reinhardt, R. L., van Rooijen, N., Wakil, A. E., Peters, M., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci68182 · Cited by 90 · see citing works
“Notably, a recent publication suggests that signaling via TLR9 might contribute to the development of these hepatic lymphoid structures (40).”
BackgroundImmune surveillance of the liver by T cells
Ficht, X., & Iannacone, M. (2020) · Science immunology · doi:10.1126/sciimmunol.aba2351 · Cited by 74 · see citing works
Direct antiviral properties of TLR ligands against HBV replication in immune-competent hepatocytes
Lucifora, J., Bonnin, M., Aillot, L., Fusil, F., Maadadi, S., Dimier, L., Michelet, M., Floriot, O., Ollivier, A., Rivoire, M. L., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-23525-w · Cited by 85 · see citing works
Ma, Z., Cao, Q., Xiong, Y., Zhang, E., & Lu, M. (2018) · Vaccines · doi:10.3390/vaccines6010006 · Cited by 84 · see citing works
“Importantly, in an HBV carrier mice model established by transferring the HBV genome via an adenovirus vector, HBV removal has been achieved by DNA vaccination and intravenous administration of the TLR9 ligand by expanding HBV-specific CTLs in the liver [64].”
BackgroundMackman, R. L., Mish, M., Chin, G., Perry, J. K., Appleby, T. C., Aktoudianakis, V., Metobo, S. E., Pyun, P., Niu, C., Daffis, S., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00100 · Cited by 84 · see citing works
Liver Inflammation and Hepatobiliary Cancers.
Leone, V., Ali, A., Weber, A., Tschaharganeh, D., & Heikenwalder, M. (2021) · Trends in Cancer · doi:10.1016/j.trecan.2021.01.012 · Cited by 79 · see citing works
Eckert, C., Klein, N., Kornek, M., & Kornek, M. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00179 · Cited by 83 · see citing works
“Moreover, the appearance of novel DC population, such as monocyte-derived DCs present in iMATEs (intrahepatic myeloid-cell aggregates for T cell population expansion), participates in efficient CLT expansion within the liver (51).”
BackgroundTherapeutic vaccination for chronic hepatitis B
Kosinska, A. D., Bauer, T., & Protzer, U. (2017) · Current Opinion in Virology · doi:10.1016/j.coviro.2017.03.011 · Cited by 78 · see citing works
Self-citationThe Contribution of Non-Professional Antigen-Presenting Cells to Immunity and Tolerance in the Liver
Mehrfeld, C., Zenner, S., Kornek, M., & Kornek, M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00635 · Cited by 78 · see citing works
“While some of the non-professional APCs can trigger efficient T-cell responses, the generation of immunity is mostly related to DC populations in draining LN or monocyte-derived DCs in intrahepatic myeloid-cell aggregates for T-cell population expansion structures (92).”
BackgroundValencia-Hernandez, A., Ng, W.-Y., Ghazanfari, N., Ghilas, S., de Menezes, M. N., Holz, L. E., Huang, C., English, K., Naung, M. T., Tan, P., et al. (2020) · Cell Host and Microbe · doi:10.1016/j.chom.2020.04.010 · Cited by 71 · see citing works
Tissue CD14+CD8+T-cells reprogrammed by myeloid cells and modulated by LPS
Pallett, L., Swadling, L., Diniz, M., Maini, A. A., Schwabenland, M., Gasull, A. D., Davies, J., Kucykowicz, S., Skelton, J., Thomas, N., et al. (2023) · Nature · doi:10.1038/s41586-022-05645-6 · Cited by 68 · see citing works
Alternative splicing of hepatitis B virus: A novel virus/host interaction altering liver immunity
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“Additionally, monocytes/macrophages could participate in HBV specific adaptive immunity through the formation of intrahepatic myeloid-cell aggregates enabling local CD8 T cells expansion (iMATEs)[41, 42].”
Immunopathogenesis of Hepatitis B Virus
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“In a mouse model of persistent HBV infection, systemic administration of TLR9 agonist induced formation of intrahepatic myeloid-cell aggregates for T-cell population expansion in the liver, which facilitated intrahepatic expansion of HBV-specific CD8+ T cells derived from the HBV vaccine and clearance of the persisten…”
BackgroundSelf-citationLiu, J., Jiang, M., Ma, Z.-Y., Dietze, K. K., Zelinskyy, G., Yang, D.-L., Dittmer, U., Schlaak, J., Roggendorf, M., & Lu, M.-J. (2013) · Journal of Immunology · doi:10.4049/jimmunol.1301262 · Cited by 69 · see citing works
“Very recent study has demonstrated signaling via TLRs induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (37).”
BackgroundNovel Indications for Fecal Microbial Transplantation: Update and Review of the Literature
Cohen, N. A., & Maharshak, N. (2017) · Digestive Diseases and Sciences · doi:10.1007/s10620-017-4535-9 · Cited by 65 · see citing works
“In mouse models, bacterial CpG-DNA, through the TLR-9 pathway, enables hepatic expansion of HBV-specific cytotoxic CD8 T cells and thus eradicates chronic infection [71].”
Human Hepatocytes and Hematolymphoid Dual Reconstitution in Treosulfan-Conditioned uPA-NOG Mice
Gutti, T. L., Knibbe, J., Makarov, E., Zhang, J., Yannam, G. R., Gorantla, S., Sun, Y., Mercer, D. F. F., Suemizu, H., Wisecarver, J. L., et al. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.09.008 · Cited by 66 · see citing works
TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury
Lan, P., Fan, Y., Zhao, Y., Lou, X., Monsour, H., Zhang, X., Choi, Y., Dou, Y., Ishii, N., Ghobrial, R. M., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci91075 · Cited by 64 · see citing works
Tzeng, H.-T., Tsai, H.-F., Chyuan, I., Liao, H., Chen, C., Chen, P., & Hsu, P. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103008 · Cited by 62 · see citing works
“In addition, TNF alpha is the key mediator that drives local intrahepatic proliferation of T cells (iMATEs: ‘intrahepatic myeloid-cell aggregates for T cell population expansion’) [36], and the effect of TNF in HBV clearance in this mouse model could be due to such iMATEs.”
BackgroundProspects for the Global Elimination of Hepatitis B
Block, T. M., Chang, K., & Guo, J. (2021) · Annual Review of Virology · doi:10.1146/annurev-virology-091919-062728 · Cited by 59 · see citing works
Faure‐Dupuy, S., Lucifora, J., & Durantel, D. (2017) · Viruses · doi:10.3390/v9050095 · Cited by 58 · see citing works
“By order of decreasing abundance, innate cells from: (1) lymphoid origin (natural killer and natural killer T-cells (NK/NKT) but also innate lymphoid cells (ILC), and mucosal-associated invariant T-cell (MAIT)); (2) myeloid origin (e.g., Kupffer cells (KCs), myeloid-derived suppressive cells (MDSC), monocytes, neutrop…”
BackgroundInfluentialLi, L., Barry, V., Daffis, S., Niu, C., Huntzicker, E. G., French, D. M., Mikaelian, I., Lanford, R. E., Delaney, W. E., & Fletcher, S. P. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.12.008 · Cited by 58 · see citing works
“myeloid cells that facilitate expansion of CTLs in the liver of mice [12].”
BackgroundInfluentialDissecting the dendritic cell controversy in chronic hepatitis B virus infection
Gehring, A. J., & D’Angelo, J. A. (2014) · Cellular and Molecular Immunology · doi:10.1038/cmi.2014.95 · Cited by 57 · see citing works
Neumann, K., Rudolph, C., Neumann, C., Janke, M., Amsen, D., & Scheffold, A. (2015) · European Journal of Immunology · doi:10.1002/eji.201445346 · Cited by 53 · see citing works
In Vivo Mouse Models for Hepatitis B Virus Infection and Their Application
Du, Y., Broering, R., Li, X., Zhang, X., Liu, J., Yang, D., & Lu, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.766534 · Cited by 56 · see citing works
“In acute HBV infection in humans, viral clearance is associated with the development of a vigorous multispecific CD8+ T cell response and an acute necroinflammatory liver disease; it was therefore assumed that HBV clearance is principally mediated by virus-specific major Frontiers in Immunology | www.frontiersin.org 3…”
BackgroundImmune outcomes in the liver: Is CD8 T cell fate determined by the environment?
Wong, Y. C., Tay, S. S., McCaughan, G. W., Bowen, D. G., & Bertolino, P. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.05.033 · Cited by 55 · see citing works
“1008 Journal of Hepatology 2015 myeloid cells into the liver to form microanatomical structures that support expansion of activated T cells independent of antigen specificity [48].”
BackgroundControl and Eradication Strategies of Hepatitis B Virus
Shih, C., Chou, S.-F., Yang, C.-C., Huang, J., Choijilsuren, G., & Jhou, R. (2016) · Trends in Microbiology · doi:10.1016/j.tim.2016.05.006 · Cited by 53 · see citing works
The liver as a central "hub" of the immune system: pathophysiological implications
Ronca, V., Gerussi, A., Collins, P., Parente, A., Oo, Y. H., & Invernizzi, P. (2025) · Physiological Reviews · doi:10.1152/physrev.00004.2023 · Cited by 59 · see citing works
Immune Therapeutic Strategies in Chronic Hepatitis B Virus Infection: Virus or Inflammation Control?
Bertoletti, A., & Gehring, A. J. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003784 · Cited by 52 · see citing works
“TLR agonists [20] results in effective T cell expansion in murine”
InfluentialMacrophages as key regulators of liver health and disease
Papachristoforou, E., & Ramachandran, P. (2022) · International review of cytology · doi:10.1016/bs.ircmb.2022.04.006 · Cited by 55 · see citing works
Selective expansion of myeloid and NK cells in humanized mice yields human-like vaccine responses
Douam, F., Ziegler, C. G. K., Hrebikova, G., Fant, B., Leach, R. W., Parsons, L. R., Wang, W., Gaska, J. M., Winer, B. Y., Heller, B. L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07478-2 · Cited by 51 · see citing works
Liu, J., Yu, Q., Wu, W., Huang, X., Broering, R., Werner, M., Roggendorf, M., Yang, D., & Lu, M. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1700540 · Cited by 50 · see citing works
“For example, TLR9 ligand CpG was reported to be able to induce the formation of intrahepatic myeloid cell aggregates for T cell population expansion (termed iMATEs) (33).”
BackgroundHöchst, B., Mikulec, J., Baccega, T., Metzger, C., Welz, M., Peusquens, J., Tacke, F., Knolle, P. A., Kurts, C., Diehl, L., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119662 · Cited by 52 · see citing works
“Isolation of liver non-parenchymal cells was performed as described before [27].”
MethodSelf-citationImmune Cell Trafficking to the Liver
Chaudhry, S., Emond, J. C., & Griesemer, A. D. (2019) · Transplantation · doi:10.1097/tp.0000000000002690 · Cited by 50 · see citing works
“However, TLR response to pathogenic infections leads to recruitment of neutrophils and a potent inflammatory response.(40,79-81) LSECs have abundant expression of both scavenger and carbohydrate receptors.”
BackgroundMovita, D., van de Garde, M. D. B., Biesta, P. J., Kreefft, K., Haagmans, B. L., Zúñiga, E. I., Herschke, F., Jonghe, S. D., Janssen, H. L. A., Gama, L., et al. (2015) · Journal of Virology · doi:10.1128/jvi.03733-14 · Cited by 48 · see citing works
“Recently, the formation of intrahepatic myeloid cell aggregates that can stimulate local T cell proliferation (iMATE) has been attributed to monocyte-derived TNF (46).”
BackgroundMa, Z., Liu, J., Wu, W., Zhang, E., Zhang, X., Li, Q., Zelinskyy, G., Buer, J., Dittmer, U., Kirschning, C. J., et al. (2017) · Cellular and Molecular Immunology · doi:10.1038/cmi.2017.43 · Cited by 48 · see citing works
Chang, J., & Guo, J. (2015) · Antiviral Research · doi:10.1016/j.antiviral.2015.07.006 · Cited by 47 · see citing works
“The antiviral immune response reduced HBV antigeniemia and eventually eliminated HBV-replicating hepatocytes (Huang et al., 2013).”
Humoral immunity in hepatitis B virus infection: Rehabilitating the B in HBV
Vanwolleghem, T., Adomati, T., Hees, S. V., & Janssen, H. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100398 · Cited by 48 · see citing works
“the addition of a TLR9 adjuvant to therapeutic vaccines in animal models of CHB led to control of viral replication via intrahepatic proliferation of cytotoxic CD8 T cells in so-called intrahepatic myeloid-cell aggregates (iMATEs).(119,120) Importantly, these iMATEs did not require the presence of B cells, as they wer…”
BackgroundBarreiro, O., Cibrián, D., Clemente, C., Álvarez, D., Moreno, V., Valiente, Í., Bernad, A., Vestweber, D., Arroyo, A. G., Martı́n, P., et al. (2016) · eLife · doi:10.7554/elife.15251 · Cited by 45 · see citing works
“…macrophages in lymph nodes and Kupffer cells in liver, can traverse fenestrated endothelial sinusoids to capture lymph- or blood-borne particulate antigens and participate in the initiation of innate and adaptive immunity (Huang et al., 2013; Junt et al., 2007; Lee et al., 2010; Wong et al., 2013).”
BackgroundAn OX40/OX40L interaction directs successful immunity to hepatitis B virus
Publicover, J., Gaggar, A., Jespersen, J. M., Halac, U., Johnson, A. J., Goodsell, A., Avanesyan, L., Nishimura, S. L., Holdorf, M. M., Mansfield, K. G., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aah5766 · Cited by 43 · see citing works
Self-citationStaying local-antigen presentation in the liver
Knolle, P. A. (2016) · Current Opinion in Immunology · doi:10.1016/j.coi.2016.02.009 · Cited by 42 · see citing works
Self-citationNK cells limit therapeutic vaccine–induced CD8 + T cell immunity in a PD-L1–dependent manner
Diniz, M. O., Schurich, A., Chinnakannan, S. K., Duriez, M., Stegmann, K. A., Davies, J. E., Kucykowicz, S., Suveizdytė, K., Amin, O. E., Alcock, F., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abi4670 · Cited by 43 · see citing works
“An adenoviral vector encoding the HBV genome (Ad-HBV) was injected intravenously to establish persistent low-level HBV infection in the hepatocytes of immunocompetent C57BL/6 mice, as described previously (23, 24).”
MethodImmunometabolic cues recompose and reprogram the microenvironment around implanted biomaterials
Maduka, C. V., Schmitter-Sánchez, A. D., Makela, A. V., Ural, E. E., Stivers, K. B., Pope, H., Kuhnert, M. M., Habeeb, O. M., Tundo, A., Alhaj, M., et al. (2024) · Nature Biomedical Engineering · doi:10.1038/s41551-024-01260-0 · Cited by 43 · see citing works
“1p), we sought to uncover the relative contribution of myeloid cells, including CD11b + monocytes 39–41 (CD11b could also be expressed on subsets of B cells, neutrophils and macrophages 42 ), F4/80 + macrophages 42 and CD11c + dendritic cells 43,44 , to the constitution and polarization of the…”
Animal Models Used in Hepatitis C Virus Research
Berggren, K. A., Suzuki, S., & Ploß, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113869 · Cited by 42 · see citing works
“Such co-engraftments could enhance T and B cell selection, intra-hepatic T cell priming [160] and liver-mediated secretion of key human-immune components [161].”
BackgroundTian, M., Liu, W.-R., Wang, H., Zhou, Y., Jin, L., Jiang, X., Tao, C.-Y., Tang, Z., Zhou, P., Fang, Y., et al. (2019) · BMC Medicine · doi:10.1186/s12916-019-1341-6 · Cited by 41 · see citing works
Toll-like receptor-mediated innate immunity orchestrates adaptive immune responses in HBV infection
Du, Y., Wu, J., Liu, J., Zheng, X., Yang, D., & Lu, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.965018 · Cited by 39 · see citing works
“reported that TLR signaling induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs during chronic viral liver infection (88).”
BackgroundWu, L., Peng, W., Wu, H., Miaw, S., Yeh, S., Yang, H., Liao, P.-H., Lin, J., Chen, Y., Hong, Y., et al. (2019) · Hepatology · doi:10.1002/hep.30510 · Cited by 39 · see citing works
Intestinal Microbiota—A Promising Target for Antiviral Therapy?
Yang, M., Yang, Y., He, Q., Zhu, P., Liu, M., Xu, J., & Zhao, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.676232 · Cited by 41 · see citing works
“Nevertheless, bacterial CpG-DNA (a TLR9 ligand) overrides liver tolerance through CpG-DNA/TLR9, increasing the expansion of HBV-specific cytotoxic CD8 T cells and leading to virus clearance (96).”
BackgroundKosinska, A. D., Moeed, A., Kallin, N., Festag, J., Su, J., Steiger, K., Michel, M., Protzer, U., & Knolle, P. A. (2019) · Scientific Reports · doi:10.1038/s41598-019-47149-w · Cited by 38 · see citing works
Self-citationHarnessing the liver to induce antigen-specific immune tolerance
Gottwick, C., Carambia, A., & Herkel, J. (2022) · Seminars in Immunopathology · doi:10.1007/s00281-022-00942-8 · Cited by 37 · see citing works
Drugs in Development for Hepatitis B
Dawood, A., Basit, S. A., Jayaraj, M., & Gish, R. G. (2017) · Drugs · doi:10.1007/s40265-017-0769-2 · Cited by 35 · see citing works
Wei, L., Zhao, T., Zhang, J., Mao, Q., Gong, G., Sun, Y., Chen, Y., Wang, M., Tan, D., Gong, Z., et al. (2021) · Hepatology · doi:10.1002/hep.32109 · Cited by 35 · see citing works
“[31,32] Targeting innate immunity has been demonstrated to increase HBV- specific adaptive responses in mice and humans.[33,34] Therefore, using empty liposome as placebo may curtail the statistical difference of εPA- 44; hence, empty liposome is not used as placebo in our ongoing phase 3 trial.”
MethodRole of T cells in liver metastasis
Wu, K., Zhang, G., Shen, C., Zhu, L., Yu, C., Sartorius, K., Ding, W., Jiang, Y., & Lu, Y. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06726-2 · Cited by 35 · see citing works
“In the presence of PD-L1, activated CD8 + T cells do not develop into cytotoxic cells but instead exhibit an anergic state [42].”
BackgroundCX3CR1 Mediates the Development of Monocyte-Derived Dendritic Cells during Hepatic Inflammation
Sutti, S., Bruzzì, S., Heymann, F., Liepelt, A., Krenkel, O., Toscani, A., Ramavath, N., Cotella, D., Albano, E., & Tacke, F. (2019) · Cells · doi:10.3390/cells8091099 · Cited by 34 · see citing works
- Authors
- Huang, L.-R., Wohlleber, D., Reisinger, F., Jenne, C. N., Cheng, R.-L., Abdullah, Z., Schildberg, F. A., Odenthal, M., Dienes, H.-P., van Rooijen, N., Schmitt, E., Garbi, N., Croft, M., Kurts, C., Kubes, P., Protzer, U., Heikenwalder, M., & Knolle, P. A.
- Affiliations
- University of Bonn (DE)
- Helmholtz Munich (DE)
- University of Calgary (CA)
- University of Cologne (DE)
- Johannes Gutenberg University Mainz (DE)
- La Jolla Institute for Immunology (US)
- Corresponding author
- Knolle, Percy A
- ORCID
- Venue
- Nature Immunology
- Published
- 2013-04-14
- Volume
- 14
- Issue
- 6
- Pages
- 574-583
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2049247030
- Cited by
- 216
- References
- 38
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 13 · 2023: 13 · 2022: 12 · 2021: 17 · 2020: 13 · 2019: 16 · 2018: 30 · 2017: 23 · 2016: 24 · 2015: 19 · 2014: 15 · 2013: 9
- FWCI
- 12.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Keywords
- CD8+ T cell proliferation, Toll-like receptor signaling, TNF-α, cytotoxic T lymphocytes, DNA vaccine, immunotherapy, liver
- MeSH terms
- Animals, Animals, Newborn, Chronic Disease, Flow Cytometry, Immunotherapy, Liver, Liver Diseases, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Inbred C57BL, Mice, Transgenic, T-Lymphocytes, Cytotoxic, Signal Transduction, Mice, Knockout, CD8-Positive T-Lymphocytes, Microscopy, Confocal, Myeloid Cells, CD11b Antigen, Cell Proliferation, Green Fluorescent Proteins, Toll-Like Receptor 9, Mice, Receptors, OX40, Host-Pathogen Interactions
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