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Updated: May 21, 2026
Use of In vivo Imaging to Monitor the Progression of Experimental Mouse Cytomegalovirus Infection in Neonates
Published on: July 6, 2013
Efficient human cytomegalovirus reactivation is maturation dependent in the Langerhans dendritic cell lineage and can
Margaret M Huang1, Verity G Kew, Kevin Jestice
1Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
Abstract:
Studies from a number of laboratories have shown that the myeloid lineage is prominent in human cytomegalovirus (HCMV) latency, reactivation, dissemination, and pathogenesis. Existing as a latent infection in CD34(+) progenitors and circulating CD14(+) monocytes, reactivation is observed upon differentiation to mature macrophage or dendritic cell (DC) phenotypes. Langerhans' cells (LCs) are a subset of periphery resident DCs that represent a DC population likely to encounter HCMV early during primary infection. Furthermore, we have previously shown that CD34(+) derived LCs are a site of HCMV reactivation ex vivo. Accordingly, we have utilized healthy-donor CD34(+) cells to study latency and reactivation of HCMV in LCs. However, the increasing difficulty acquiring healthy-donor CD34(+) cells--particularly from seropositive donors due to the screening regimens used--led us to investigate the use of CD14(+) monocytes to generate LCs. We show here that CD14(+) monocytes cultured with transforming growth factor β generate Langerin-positive DCs (MoLCs). Consistent with observations using CD34(+) derived LCs, only mature MoLCs were permissive for HCMV infection. The lytic infection of mature MoLCs is productive and results in a marked inhibition in the capacity of these cells to promote T cell proliferation. Pertinently, differentiation of experimentally latent monocytes to the MoLC phenotype promotes reactivation in a maturation and interleukin-6 (IL-6)-dependent manner. Intriguingly, however, IL-6-mediated effects were restricted to mature LCs, in contrast to observations with classical CD14(+) derived DCs. Consequently, elucidation of the molecular basis behind the differential response of the two DC subsets should further our understanding of the fundamental mechanisms important for reactivation.
Insights
Human cytomegalovirus (HCMV) reactivation occurs in mature myeloid cells. This study shows that monocytes can differentiate into Langerhans cells (LCs) that support HCMV latency and reactivation, offering a new model for studying viral pathogenesis.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Human cytomegalovirus (HCMV) establishes latency in myeloid cells, including CD34(+) progenitors and CD14(+) monocytes.
- Reactivation of HCMV from latency is linked to the differentiation of these myeloid cells into mature macrophage or dendritic cell (DC) phenotypes.
- Langerhans' cells (LCs), a subset of peripheral DCs, are likely encountered early during primary HCMV infection and have been shown to support viral reactivation ex vivo.
Purpose of the Study:
- To investigate the utility of CD14(+) monocytes as a source for generating Langerhans-like cells (MoLCs) for studying HCMV latency and reactivation.
- To characterize HCMV permissiveness, infection dynamics, and reactivation in MoLCs.
- To compare the role of interleukin-6 (IL-6) in HCMV reactivation between MoLCs and classical CD14(+) derived DCs.
Main Methods:
- Generation of Langerin-positive DCs (MoLCs) from CD14(+) monocytes using transforming growth factor β.
- Infection of mature MoLCs with HCMV to assess permissiveness and viral replication.
- Evaluation of the impact of HCMV infection on MoLCs' capacity to promote T cell proliferation.
- Induction of experimental latency in monocytes followed by differentiation to MoLCs to study reactivation.
- Assessment of IL-6-dependent reactivation in mature MoLCs and comparison with classical DCs.
Main Results:
- CD14(+) monocytes successfully differentiated into Langerin-positive MoLCs.
- Only mature MoLCs were permissive for HCMV infection, supporting productive lytic infection.
- HCMV infection of mature MoLCs significantly inhibited their ability to promote T cell proliferation.
- Differentiation of latently infected monocytes to MoLCs promoted HCMV reactivation in a maturation and IL-6-dependent manner.
- IL-6-mediated reactivation effects were specific to mature MoLCs, differing from classical CD14(+) derived DCs.
Conclusions:
- CD14(+) monocyte-derived LCs (MoLCs) provide a viable alternative model for studying HCMV latency and reactivation, overcoming challenges in obtaining CD34(+) cells.
- Mature MoLCs are permissive to HCMV infection and support viral reactivation, with implications for viral pathogenesis and immune evasion.
- The differential regulation of IL-6-mediated reactivation between MoLCs and classical DCs highlights subset-specific mechanisms crucial for understanding HCMV persistence.
