Human Cytomegalovirus Infection Promotes Expansion of a Functionally Superior Cytoplasmic CD3+ NK Cell Subset with a Bcl11b-Regulated T Cell Signature.

Human CMV (HCMV) is a ubiquitous pathogen that indelibly shapes the NK cell repertoire. Using transcriptomic, epigenomic, and proteomic approaches to evaluate peripheral blood NK cells from healthy human volunteers, we find that prior HCMV infection promotes NK cells with a T cell-like gene profile, including the canonical markers CD3ε, CD5, and CD8ß, as well as the T cell lineage-commitment transcription factor Bcl11b. Although Bcl11b expression is upregulated during NK maturation from CD56bright to CD56dim, we find a Bcl11b-mediated signature at the protein level for FcεRIγ, PLZF, IL-2Rß, CD3γ, CD3δ, and CD3ε in later-stage, HCMV-induced NK cells. BCL11B is targeted by Notch signaling in T cell development, and culture of NK cells with Notch ligand increases cytoplasmic CD3ε expression. The Bcl11b-mediated gain of CD3ε, physically associated with CD16 signaling molecules Lck and CD247 in NK cells is correlated with increased Ab-dependent effector function, including against HCMV-infected cells, identifying a potential mechanism for their prevalence in HCMV-infected individuals and their prospective clinical use in Ab-based therapies.

Methods of Mesenchymal Stem Cell Homing to the Blood-Brain Barrier.

Mesenchymal stem/stromal cells (MSC) are multipotent cells that can be isolated from adult and fetal tissues. In vitro, MSCs show functional plasticity by differentiating into specialized cells of all germ layers. MSCs are of relevant to medicine and have been proposed for several disorders. MSCs can be transplanted across allogeneic barriers as "off the shelf" cells. This chapter focuses on methods to deliver MSCs to the brain because neurological pathology such as damage due to stroke can lead to debilitating mental and physical problems. In general, neurological diseases are difficult to treat, partly due to the challenge in getting drugs across the blood-brain barrier (BBB). MSCs as well as other stem cells can cross the BBB. The described method begins to develop procedures, leading to efficient delivery of drugs to the brain. Here describe how MSCs can be propagated from bone marrow aspirates and their utility in delivering small RNA to the brain. The chapter discusses the issue to enhance efficient delivery of MSCs to the brain.