No monkey business: why studying NK cells in non-human primates pays off

Henoch S Hong,R Paul Johnson,Premeela A Rajakumar,James M Billingsley,R Keith Reeves

doi:10.3389/fimmu.2013.00032

Abstract

Human NK (hNK) cells play a key role in mediating host immune responses against various infectious diseases. For practical reasons, the majority of the data on hNK cells has been generated using peripheral blood lymphocytes. In contrast, our knowledge of NK cells in human tissues is limited, and not much is known about developmental pathways of hNK cell subpopulations in vivo. Although research in mice has elucidated a number of fundamental features of NK cell biology, mouse, and hNK cells significantly differ in their subpopulations, functions, and receptor repertoires. Thus, there is a need for a model that is more closely related to humans and yet allows experimental manipulations. Non-human primate models offer numerous opportunities for the study of NK cells, including the study of the role of NK cells after solid organ and stem cell transplantation, as well as in acute viral infection. Macaque NK cells can be depleted in vivo or adoptively transferred in an autologous system. All of these studies are either difficult or unethical to carry out in humans. Here we highlight recent advances in rhesus NK cell research and their parallels in humans. Using high-throughput transcriptional profiling, we demonstrate that the human CD56bright and CD56dim NK cell subsets have phenotypically and functionally analogous counterparts in rhesus macaques. Thus, the use of non-human primate models offers the potential to substantially advance hNK cell research.

Highlights

THE NEED FOR A BETTER MODEL TO UNDERSTAND HUMAN NK CELLS NK cells are lymphocytes that have evolved to provide a first line of immune protection against viruses and malignancies before adaptive immune responses emerge (Lanier, 2008)
Using high-throughput transcriptional profiling, we demonstrate that the human CD56bright and CD56dim NK cell subsets have phenotypically and functionally analogous counterparts in rhesus macaques
These studies suggest that a better knowledge of human NK (hNK) cells has the potential to be translated into novel, therapeutic approaches, research has been hindered by the limitations of the human “model.” Most of our knowledge on hNK cells has been derived from studies performed on peripheral blood lymphocytes due to ease of accessibility

Summary

DEFINING NK CELL SUBPOPULATIONS IN RHESUS MACAQUES

Unlike hNK cells, virtually all rmNK cells in peripheral blood express CD8α and most of them do not express CD56 (Carter et al, 1999). The CD16+ rmNK cell population corresponds well to the CD56dim hNK cell subset, as evidenced by the increased expression of granzyme B and perforin and absence of CCR7 and CD62L. A previous transcriptome analysis study revealed a number of differentially expressed genes in CD56bright and CD56dim hNK cells (Hanna et al, 2004). This is of particular interest since increasing evidence suggests that CD56bright NK cells represent a less mature developmental stage of NK differentiation, whereas CD56dim cells exhibit a more differentiated effector profile (Romagnani et al., 2007; Yu et al, 2010; Beziat et al, 2011). A number of potential candidates have been suggested as intermediate NK cell populations in humans, including CD16+CD56bright cells

Relative Expression

Increasing Differentiation

CONCLUSION