Diversification of human NK cells: Lessons from deep profiling

Abstract

NK cells are innate lymphocytes with important roles in immunoregulation, immunosurveillance, and cytokine production. Originally defined on the functional basis of their "natural" ability to lyse tumor targets and thought to be a relatively homogeneous group of lymphocytes, NK cells possess a remarkable degree of phenotypic and functional diversity due to the combinatorial expression of an array of activating and inhibitory receptors. Diversification of NK cells is multifaceted: mechanisms of NK cell education that promote self-tolerance result in a heterogeneous repertoire that further diversifies upon encounters with viral pathogens. Here, we review the genetic, developmental, and environmental sources of NK cell diversity with a particular focus on deep profiling and single-cell technologies that will enable a more thorough and accurate dissection of this intricate and poorly understood lymphocyte lineage.

NK cell immune responses differ after prime and boost vaccination

“…The remaining 7 phenotypic families (, and ) displayed strong interindividual variability in their dynamics and various patterns. Phenotypic family 10 notably only showed a very low peak at D14PP.…”

“…C). The wide diversity of the NK cell receptor repertoire, for which each combination of NK cell receptors can virtually give rise to a new subset of NK cells, was recently uncovered . However,the meaning of such NK cell diversity for vaccines is not yet understood.…”

“…NK cells are innate lymphoid cells that can constitutively kill cells carrying an abnormal MHC signature, via interactions of activating and inhibitory receptors between NK cells and their targets . The wide diversity of the NK cell receptor repertoire implies a large range of potential NK cell subpopulations . NK cells exhibit numerous functions other than cytotoxicity, including modulation of the behavior of other innate and adaptive immune cell populations, such as through cross‐talk with dendritic cells (DCs) or cytokine production .…”

Data analysis to modeling to building theory in NK cell biology and beyond: How can computational modeling contribute?

“…Can these models be used to unify a broad range of features in NK cell biology? It is difficult to give a straightforward answer to this question in the face of new details about NK cell biology that are emerging from recent single cell and sequencing measurements . These multidimensional datasets may lead to revision of assumptions and approximations made in these models, and some of the new data could be incompatible with these models as many of these models’ behaviors are sensitive to changes in key assumptions or parameter values …”

“…Diverse NK cell populations (e.g., educated or uneducated NK cells, “memory” NK cells) appear to be relevant for controlling viral infections such as HCMV infection or proliferation of tumor cells or graft rejection. High‐dimensional datasets such as RNA‐seq data describing changes in NK cell gene expressions NKR gene sequences, and protein expressions in single NK cells (e.g., CyTOF) provide detailed description regarding the involvement of NK cell populations in immune responses elicited by a viral infection or by an organ transplant. Data‐driven models are being increasingly applied to develop predictive computational frameworks to determine precision biomarkers in patients for optimizing NK cell and T cell responses in immunotherapies or organ transplants.…”