Immunological their longevity through self-renewal until a subsequent encounter

Immunological
memory is a cardinal feature of adaptive immunity. Although natural killer (NK)
cells have long been considered short-lived innate lymphocytes that respond
rapidly to transformed and virus-infected cells without prior sensitization.(1)
It has recently become appreciated that NK cells can also acquire functional
qualities commonly associated with immunological memory similar to that of T
and B cells in response to pathogens and in non-infectious settings.(2)

Antigen-specific
memory NK cell responses were first observed in a murine model of
hapten-induced CHS (3). This model was established through sensitization via
painting a specific hapten, such as 2,4-dinitrofluorobenzene (DNFB) or
oxazolone (OXA), on mouse skin and subsequent challenge with the same hapten on
the ears of the mice, after which the recall responses to the haptens were
measured based on ear swelling.(4,5)

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The
ability of the immune system to respond rapidly and provide enhanced protection
of the host against a previously encountered pathogen is defined classically as
immunological memory. Longlived memory cells are generated after initial
infection and display heightened responses upon secondary challenge with the
same pathogen. The process of memory formation in T cells has been well studied
and is generally divided into three distinct phases. Upon exposure to cognate
antigen, naive CD8+ T cells clonally expand and differentiate into effector
cells during the ”expansion” phase. This first phase is followed by a rapid
”contraction” phase, when the vast majority of effector CD8+ T cells undergo
apoptosis to form a small, but stable, pool of surviving cells that then enter
the third ”memory” phase. Memory CD8+ T cells persist throughout the host organs
and maintain their longevity through self-renewal until a subsequent encounter
with their cognate antigen, when they exhibit enhanced effector function and
host protection. In an experimental system in which Ly49H+ NK cells were
adoptively transferred into mice lacking this receptor, these Ly49H+ cells
underwent robust antigen-driven expansion after MCMV infection. Similar to
activated CD4+ T cells, expanded effector NK cells undergo a slower and
sustained contraction phase to establish a long-lived and
self-renewing ”memory” pool of antigen-specific NK cells that can be
recovered many months after infection in a variety of peripheral tissues. (6)

In
the following section, we summarized the receptors, cytokines and signalling
pathways that have been impli­cated in the development of memory NK cells:

 

1.     
Hapten-specific
memory NK cells: Following sensitization of mice with haptens,
hapten-specific memory natural killer (NK) cells are detected in the liver. The
generation of these memory NK cells is dependent on the cytokines interleukin?12
(IL?12), interferon?? (IFN?) and IFN?. Antibody-mediated blockade of the NK
cell receptor natural killer group 2, member D (NKG2D) or CXC-chemokine
receptor 6 (CXCR6), or molecules that are involved in NK cell trafficking (such
as CD18 and P- and E?selectin) prevents the development of contact
hypersensitivity (CHS) responses in the ear after hapten challenge.(3,7,8)

2.     
MCMV-specific
memory NK cells: During mouse cytomegalovirus (MCMV)-infection,
naive NK cells expressing the LY49H receptor expand with contribution of
signalling mediated by the DNAX accessory molecule 1 (DNAM1) receptor and the
inflammatory cytokines IL?12, IL?18 and IL?33. Inflammatory cytokines drive the
expression of zinc finger and BTB domain-containing 32 (ZBTB32) and the
microRNA miR?155, which are involved in the expansion of ‘effector’ NK cells.
Following the elimination of the virus, the BIM and autophagy pathways regulate
the contraction of the expanded populations of NK cells, giving rise to a
population of MCMV-specific memory NK cells. Although MCMV-specific memory NK
cells distribute systemically in mice, memory NK cells specific for vaccinia
virus reside in the liver, and influenza virus-specific memory NK cells are
found in the liver and lungs (not shown). In non-human primates, simian
immunodeficiency virus-specific memory NK cells reside in the spleen and liver.(9,10,11,12,13,14)

3.      Cytokine-induced memory NK cells: In vitro, the
brief exposure of NK cells to the cytokines IL?12, IL?15 and IL?18 results in
the upregulation of IFN?, perforin and granzymes, and the production of high
levels of CD25, the high-affinity ?-chain of the IL?2 receptor, is also
induced. After adoptive transfer, these cytokine-induced memory NK cells
persist long term, and their ability to produce abundant cytokines and express
perforin and granzymes is maintained. The presence of IL?2 (or IL?15) further
increases NK cell numbers and their ability to express IFN?, perforin and granzymes
after adoptive transfer.(15,16,17,18)