NK Cells: Do these cells have Memory? (Part 1)

Introduction: A Primer


Memory

The ability of the immune system to recognize previously encountered pathogens and initiate a better immune response is the hallmark of memory. Responses to previously encountered organisms are characterized by, among other things, a large clonal population of cells that are uniquely specific for the offending pathogen. As an oversimplification, this large population then out-competes the rate of pathogen spread and brings the infection under control.

These memory populations have been thought to come from the adaptive immune system, consisting of both B and T cells. Upon primary infection, naive B and T cells specific for the pathogen exist at low precursor frequency. In order to be activated and clonally expand into a large effector population, these cells must be activated by the innate immune system, which provides the necessary co-stimulation in order to fully induce an adaptive response. Immune system responses can be thought of as a game of escalation: the innate arm recognizes pathogen-associated molecular patterns common to most pathogens and responds early in the infection process. If, however, the innate system is unable to control pathogen spread, it activates the adaptive immune system. Once activated, B and T cells expand into large number of cells directed against the specific pathogen, proceeding to contract into a small population of memory cells after clearance of antigen. These memory cells protect against future infection (or damage to the host) through a variety of ways

Inducing memory (and thus a B and T cell response) is the mechanism by which vaccines work.


NK cells

Natural killer cells are part of the innate immune system. Like all innate cells, NK cells are characterized by their ability to recognize patterns and respond early in infection. However, unlike macrophages and dendritic cells, NK cells do not interact directly with pathogens.* Instead, they recognize patterns on host cells associated with cellular abnormality, which can either be induced by viral infection or if the cell has become cancerous.

NK cells have both activating and inhibitory receptors on their surface which provide the ability to surveil the state of the host. These receptors interact with ligands on other cells and the combined signal from both types of receptors ultimately determine the response from the NK cell. If there are more inhibitory signals than activating ones, the NK cell does not respond. If, however, there are more activating stimuli, any inhibitory signal is overrode and the NK cell carriers out its effector function (death of the target cell, cytokine production). Examples of activating ligands include cellular stress molecules expressed during virus infection. In another example, the absence of an important inhibitory molecule called MHC is an indication that there is something wrong with the cell.

Because NK cells possess a limited set of receptors that respond to patterns of positive and negative signals instead of specific pathogens, it makes sense that these cells should not have memory. An expanded subset of relatively nonspecific NK cells (as compared to B and T cells) might actually be detrimental to the host in certain circumstances. When control can be handled by the innate arm of the immune system, inducing a large memory population of powerful NK cells might cause more damage to the host than the offending pathogen.

The Current Picture

However, within the past few years, the idea of what cell types constitute memory has been challenged. While this area is still largely the domain of B and T cells, recent evidence points to memory-like properties of NK cells such as: increased immune response to secondary encounter with antigen, adoptive transfer of NK cells providing pathogen-specific responses, and long- lived** subsets of NK cells induced by primary infection with pathogens.

In the following posts, my goal is to give a very brief introduction to this new finding.




*There are some virus-specific receptors, and we will talk about one of them in the near future.
**long-lived in this case meaning up to 90 days