HCMV Infection in a Mesenchymal Stem Cell Niche: Differential Impact on the Development of NK Cells versus ILC3

Abstract

Human cytomegalovirus (HCMV) is highly prevalent in most populations worldwide and has a major influence on shaping the human immune system. Natural killer (NK) cells are important antiviral effectors that adapt to HCMV infection by expansion of virus-specific effector/memory cells. The impact of HCMV infection on the development of NK cells and innate lymphoid cells (ILC) in general is less well understood. In this context, we have recently established a novel in vitro platform to study human NK cell development in a stem cell niche based on human bone marrow-derived mesenchymal stem cells (MSC). Here, the system was modified by infecting MSC with HCMV to study the influence of virus infection on NK/ILC development. We show that cord blood-derived hematopoietic progenitor cells are successfully differentiated into mature CD56 + CD94 + NKG2A + NK cells on HCMV-infected MSC with significant higher anti-viral cytokine production compared to NK cells developing on non-infected MSC. Furthermore, the generation of ILC3, characterized by expression of the signature transcription factor RAR-related orphan receptor gamma (RORγt) and the production of IL-22, was strongly impaired by HCMV infection. These observations are clinically relevant, given that ILC3 are associated with protection from graft-versus-host disease (GvHD) following stem cell transplantation and HCMV reactivation in turn is associated with increased incidence of GvHD.

Innate Lymphoid Cells Activation and Transcriptomic Changes in Response to Human Dengue Infection

“…Because mouse and human hILCs differ significantly ( 71 ), study in the human system is critical. Using human hILCs co-cultured with viruses in vitro , hILCs were shown to respond to rhinovirus ( 72 ), IAV ( 56 , 58 ), and human cytomegalovirus (HCMV) ( 73 ). However, the study of hILCs in natural viral infection in humans has been limited to those of HIV infection ( 74 ).…”

Mesenchymal Stem/Stromal Cells in Immunity and Disease: A Better Understanding for an Improved Use

“…Further, Elango, J. et al noted that the parathyroid hormone-related protein (PTHrP) shows accelerated soluble receptor activator of nuclear factor (NF)-kB ligand (sRANKL) downregulation of osteogenesis of MSCs, by increasing RANK expression at the earlier stage of differentiation and by inhibiting ANK [7]. On the other hand, Ising, R. et al successfully differentiated cord blood-derived hematopoietic progenitor into mature CD56+CD94+NKG2A+NK (Natural Killer) cells on HCMV (Human cytomegalovirus)-infected MSCs from bone marrow, with significantly higher anti-viral cytokine production compared to NK cells developing on non-infected MSCs [8]. Behm, C. et al observed that Vitamin D3 increases or decreases the immunomodulatory activities of Periodontal ligament-MSCs, depending qualitatively and quantitatively on the presence of specific tumor necrosis factors TNF-α-, Interleukin IL-1β-, and Interferon IFN-γ inflammatory cytokines [9].…”

Efficient In Vitro Generation of IL-22-Secreting ILC3 From CD34+ Hematopoietic Progenitors in a Human Mesenchymal Stem Cell Niche

“…The MSCbased niche enabled the highly efficient generation of NK cells including expression of KIRs, which are only scarcely generated on murine feeder cell lines (34). In the course of further studies analyzing the effect of human cytomegalovirus infection on NK cell differentiation in vitro, a NKp44 + CD56 + CD94cell subset with similarity to tissue ILC3s was identified by us (35). In the present study, we now provide compelling evidence that these cells indeed represent bona fide effector IL-22-secreting NKp44 + ILC3s and that they can be efficiently generated from umbilical CB-derived HSPC in a human MSC niche.…”