NK cells and immune "memory"

Abstract

Immunological memory is a hallmark of the adaptive immune system. However, the ability to remember and respond more robustly against a second encounter with the same pathogen has been described in organisms lacking T and B cells. Recently, NK cells have been shown to mediate Ag-specific recall responses in several different model systems. Although NK cells do not rearrange the genes encoding their activating receptors, NK cells experience a selective education process during development, undergo a clonal-like expansion during virus infection, generate long-lived progeny (i.e., memory cells), and mediate more efficacious secondary responses against previously encountered pathogens--all characteristics previously ascribed only to T and B cells in mammals. This review describes past findings leading up to these new discoveries, summarizes the evidence for and characteristics of NK cell memory, and discusses the attempts and future challenges to identify these long-lived memory NK cell populations in humans.

FIGURE 1

(A) The virus-specific NK cell response to MCMV infection. During MCMV infection, resting Ly49H⁺ NK cells become activated and undergo an expansion phase resulting in the generation of more effector cells. The expansion phase is followed by the contraction of effectors resulting in long-lived memory NK cells months after initial infection. (B) The gene array profile of different stages of the Ly49H⁺ NK cell response to MCMV infection. Congenic Ly49H⁺ NK cells were adoptively transferred prior to MCMV infection, as previously described (33). The transcriptional signature of naïve (day 0), activated (day 1.5), effector (day 7), contracting (day 14), and memory (day 30 and 50) NK cells is unique at each time point following MCMV infection. Ly49H⁺ NK cells from 3 separate mice at each time point were individually sorted on a FACSAria for RNA isolation (except for day 30 and day 50 time points done in duplicate). Samples were hybridized on the MEEBO microarray platform against reference mouse RNA, as previously described (88). All microarray data are available through the Gene Expression Omnibus under accession number GSE25672.

FIGURE 2

A comparison of CD8⁺ T cell and NK cell differentiation and memory generation following viral infection. Phenotypic and functional descriptions of resting, effector, and memory T and NK cells are shown. (lo, low; int, intermediate; hi, high)