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International Immunology, Vol. 23, No. 7, pp. 427–431
doi:10.1093/intimm/dxr035
Advance Access publication 10 June 2011
ª The Japanese Society for Immunology. 2011. All rights reserved.
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The ‘T-cell-ness’ of NK cells: unexpected similarities
between NK cells and T cells
Emilie Narni-Mancinelli1,2,3, Eric Vivier1,2,3,4 and Yann M. Kerdiles1,2,3
Centre d’Immunologie de Marseille-Luminy, Université de la Méditerranée, Campus de Luminy case 906, 13288 Marseille,
France
2
INSERM U 631, Marseille, France
3
CNRS, UMR 6102, Marseille, France
4
Assistance Publique—Hôpitaux de Marseille, Hôpital de la Conception, 13385 Marseille, France
Correspondence to: Y. M. Kerdiles; E-mail: [email protected]
Received 16 March 2011, accepted 13 May 2011
Abstract
NK cells are considered as prototypical innate immune cells. However, recent discoveries have
tended to refine the dogmatic concepts of innate and adaptive immunity. In many ways, NK cells are
highly related to T cells and represent the closest innate immune cell lineage to adaptive immune cell
populations. Here, we review the relationships between NK cells and T cells and discuss the recently
described cell-intrinsic-adaptive features of NK cells.
Keywords: adaptive immunity, innate immunity, NK cells, T cells
Introduction
Historically, the immune system of vertebrates has been
divided into two arms: the innate and the adaptive immune
systems. Whereas the innate immune system displays
a rapid response against infectious agents, the adaptive immune response involves clonal expansion and differentiation
of effector cells. Moreover, a fundamental discrepancy between the innate and adaptive immune systems relates to
the generation of immune memory in the latter whereby the
first encounter with a pathogen is remembered, allowing
a more rapid and efficient response upon re-infection with
the same pathogen. These adaptive and memory properties
were long thought to be restricted to T and B lymphocytes.
NK cells are lymphocytes of the innate immune system involved in the control of virus infection and tumor growth by
means of cytotoxicity and cytokine secretion. NK cells were
originally identified by their ability to lyse tumor cells in the
absence of specific prior sensitization. Also, unlike T and
B cells, NK cells do not express somatically re-arranged antigen-specific receptors but rely on many germ line-encoded
receptors for target recognition.
NK cells were thus classified as ‘bona fide’ innate immune
cells. Nonetheless, recent findings have revealed that NK
cells display cell-intrinsic features normally ascribed to
adaptive immune cells. Along this line, bioinformatic analyses of the transcriptional profiles of immune cells have demonstrated that NK cells are even more closely related to
T cells than any other immune cell population, including
B cells (1, 2), and many cell surface receptors originally
identified in NK cells are expressed by subsets of T cells
(3); notably, the well-know NKT cell subset, which has been
proposed to be a close variant of classical CD4 T cells
rather than an intermediate between T and NK cells (4). Illustrating the close and reciprocal relationships between NK
and T cells, these data also underpin the existence of
shared biological processes between these cell lineages.
Here, we review the common traits that exist between NK
and T cells and discuss the recently discovered involvement
of NK cells in adaptive immune responses.
Development
NK cells represent the third lymphocyte population in addition to T and B cells. NK cell development is thought to proceed through the sequential differentiation of hematopoietic
stem cells into the common lymphoid progenitor and subsequently into NK cell progenitors (NKPs).
Years ago, a fetal thymic cell population endowed with
T and NK cell differentiation potential was identified (5, 6),
suggesting that NK cells could be derived from a bipotent
T/NK progenitor lacking B-cell potential. However, unlike
B and T cells, NK cell development does not require the expression of the recombination-activating genes (Rag1,
Rag2) and proceeds normally in ‘nude’ mice (which are
athymic and lack T cells due to mutations in Foxn1) or in human patients with SCID, who lack T and B cells (7). Suggesting that the NK cell lineage would branch out independently
of B- and T-cell commitments, NK cell development has
REVIEW
1
428 NK and T cell relationships
been shown to rely on transcription factors such as E4BP4
and Id2; the deletion of which does not drastically affect
B and T cells (8).
In addition, a putative NKP phenotype was identified in
adult bone marrow (BM) as Lin CD122+ cells (9). When cultured in vitro, these BM cells where shown to be devoid of
B- and T-cell potential while efficiently generating lytic NK
cells. Nonetheless, in vivo transfer of this cell population into
sub-lethally irradiated Il2rg / mice (which lack T, B and NK
cells) allows efficient generation of both NK and T cells but
not B cells and myeloid cells (10). Although not formally
excluding the existence of a different and ‘upstream’
more-restricted NK progenitor, these findings demonstrate
the existence of bipotent T/NK progenitors in adult BM. As
such, the definitive cell-fate choice toward the classical NKcell lineage or thymus-settling progenitors would occur after
the B-cell commitment stage.
Further underlying this close developmental relationship
between NK and T cells, a thymus-dependent NK cell lineage has recently been described. Like classical NK cells,
thymic NK cells express NK1.1 and NKp46 but not CD3,
Rag2 or Rorc. However, like T cells or T-cell progenitors,
they express CD127 (IL-7Ra), their development and homeostasis rely on Il-7 as well as Gata3 expression and their
number is strongly reduced in Foxn1 / nude mice (11).
This supports a model in which CD127+ Gata3-dependent
thymus-settling progenitors would still not be fully committed to T-cell lineage until Notch-1 engagement and could
lead to the generation of this thymic NK cell population. Finally, recent evidence indicates that deletion of the transcription factor Bcl11b in fully committed T-cell precursors
is sufficient to induce their reprogramming into cells morphologically, phenotypically, functionally and genetically related to NK cells (12).
Altogether, these data highlight that NK cells, despite being
described as a prototypical innate immune-cell lineage, are
developmentally closer to T cells than the only other
RAG-dependent and adaptive immune-cell lineage, i.e. B cells.
NK cell ‘repertoire’ and recognition of major
histocompatibility complex class I molecules
NK cell activation and inhibition is controlled by a balance of
signals transduced from NK cell-activating receptors and inhibitory receptors [e.g. Ly49 molecules in mice, killer cell immunoglobulin-like receptors (KIRs) in humans] specific for
major histocompatibility complex class I molecules (MHC-I).
Interestingly, although NK cells do not express somatically
re-arranged antigen-specific receptors like T and B cells,
their expression of cell surface receptors still relies on stochastic mechanisms leading to a ‘clonal-like’ expression of
combinations of activating and inhibitory receptors (13). Furthermore, NK and T cells represent two immune-cell lineages
that are focused on the recognition of MHC molecules.
Whereas T-cell activation is triggered through the interaction
of the TCR with a peptide–MHC complex displayed by antigen-presenting cells (APCs) or infected cells, the recognition
of MHC molecules expressed by target cells through MHC
class I-specific inhibitory receptors expressed by NK cells
prevents NK-cell activation (14).
As such, NK cells act as complementary mechanisms to
detect infected or tumoral cells that down-regulate expression of MHC-I molecules and thus preclude their detection
by CD8 T cells. It is noteworthy that the NK cell-activating
receptors KIR2DS1 in humans and Ly49P in the mouse
associate with the immunoreceptor tyrosine-based activation
motif-bearing adaptor molecule DAP12/KARAP (DNAXactivating protein of 12 kDa/killer cell-activating receptorassociated protein) and can bind MHC-I molecules as
ligands (15, 16). Some NK-activating receptors are thus directly functionally related to the TCR.
Education and tolerance
The MHC-dependent target-cell recognition strategies displayed by both NK and T cells are also associated with analogous mechanisms regarding their ‘education’ toward MHC
recognition. In a murine thymus that lacks expression of
MHC molecules, T-cell development is blocked at the double-positive stage. These non-educated T cells are immature
and unresponsive to conventional antigen but have to recognize MHC-I or MHC-II molecules in order to be rescued from
cell death by neglect and proceed to their final maturation.
In a similar way, NK cells from MHC-I-deficient mice or NK
cells that do not express receptors specific for MHC-I molecules are hyporesponsive upon stimulation (17, 18). NK and
T cells therefore demonstrate a common requirement for
MHC recognition in the acquisition of functional competency,
although, unlike thymic selection of T cells, this education
process of NK cells does not seem to be associated with
the deletion of uneducated cell ‘clone-like’ populations.
It is noteworthy that wild-type mature NK cells transferred
into an MHC-I-deficient host rapidly become hyporesponsive
to ex vivo stimulation, suggesting that the MHC-dependent
NK cell education is dynamically modulated (19, 20). Furthermore, transgenic expression of the murine cytomegalovirus (MCMV) protein m157, a viral ligand for Ly49H (an NK
cell-activating receptor in mice), is also associated with the
induction of a functional hyporesponsiveness of endogenous
or adoptively transferred Ly49H+ NK cells (21, 22). This dynamic tuning of NK cell responsiveness is reminiscent of the
anergic status of T cells under chronic stimulation, which
can be reset upon transfer into irradiated host or during
overwhelming stimulation (21, 23–25). Taken together, these
results suggest that NK and T cells also use common
strategies of adaptive peripheral tolerance upon chronic
stimulation.
Cell ‘priming’
As opposed to their original definition, it is now appreciated
that resting NK cells in human and mice are poor effectors
at steady state and must be ‘primed’ in order to display their
full effector potential. Like T cells, upon infection and inflammation, NK cells are recruited from the blood to the draining
lymphoid organs (26–28). Once there, they receive dendritic
cell-derived cytokine signals such as IL-15, leading to the
transcription of GzmB (granzyme B) and Prf1 (perforin 1)
mRNA, the formation of cytotoxic granules, the enhanced
ability to secrete IFN-c upon re-stimulation (29–31) and can
NK and T cell relationships
then re-enter the circulation and migrate to peripheral tissues (30). Therefore, similar to naive T cells and challenging
the dogmatic idea that NK cells are ‘immediate effectors’,
upon infection, these innate cells would rely on migration to
secondary lymphoid organs and dendritic cell-derived signals in order to become fully functional.
Of note, IL-18 signaling in vivo is required to maintain optimal
responsiveness of NK cells in the steady state (32). In addition, the cytokines IL-12 and IL-18 can synergize to directly activate IFN-c secretion by NK cells, therefore bypassing the
need for priming and direct recognition of infected or stressed
cells. Illustrating the reciprocal mechanisms acting between
NK and memory T cells, such IL-12/IL-18 bystander activation
has also been reported for memory CD8 T cells (33–36).
Co-stimulatory signals
T-cell activation relies on TCR triggering by antigen–MHC
complexes and co-stimulatory signals provided by APCs for
their activation, optimal proliferation and survival. Similarly,
NK cell activation can be modulated by the engagement of
co-stimulatory receptors that have been well characterized in
T-cell priming. The engagement of CD27, which is a member
of the TNF receptor superfamily and is involved in T cell activation, development and T cell-dependent antibody production by B cells, promotes NK cell proliferation and IFN-c
production (37). Inducible co-stimulator is induced following
TCR activation and is involved in T-cell activation and cytokine
production; it also enhances NKG2D-mediated cytotoxicity of
activated NK cells against tumor cells (38). Finally, the CD40
ligand (CD40L)–CD40 interaction, which provides an important co-stimulatory signal during T–APC interactions, also indirectly promotes anti-tumor effects of NK cells in vivo (39).
Effector functions
Unlike many innate immune cells, NK cells are not phagocytic
but rather display a panel of effector functions largely overlapping those of T cells. Like CD8 cytotoxic T lymphocytes, NK cells
can recognize and induce the lysis of a variety of target cells, including virally infected cells and tumor cells. Upon contact with
an appropriate target, both cell types can use perforin/granzyme-dependent as well as Fas ligand-dependent cytotoxic
mechanisms. Moreover, like CD4 T cells, a subset of hepatic NK
cells can also express TRAIL (TNF-related apoptosis-inducing ligand) (40). Beyond these cytolytic activities, the cytokinesecretion profile displayed by NK cells also paralleled those of
activated CD8 T cells and Th1 cells and included the production of large amounts of IFN-c, TNF-a and CC-chemokines,
such as CCL3 (MIP-1a), CCL4 (MIP-1b) and CCL5
(RANTES) (41).
Importantly, similar to memory T cells but in contrast to naive T cells, proliferation is not required for acquisition of effector functions by NK cells (28, 42, 43). Like memory CD8
T cells, NK cells constitutively express mRNA coding for perforin, granzyme A, granzyme B and IFN-c (29, 31, 44) and
their protein expression relies on post-translational mechanisms triggered by inflammatory cytokines such as IL-2,
IL-15 or IL-18 (29, 32). The cell-intrinsic mechanisms
responsible for the maintenance of this ‘pre-armed’ state of
429
memory CD8 T cells and NK cells are still poorly described,
and whether the same mechanisms act in both cell types
remains unknown.
Nonetheless, it is important to note that like effector and
memory CD8 T cells, mature human and mouse NK cells
constitutively express the transcription factors T-bet and
Eomesodermin. These T-box factors control Ifng, Prf1, GzmB
and Il2rb gene expression and are both critically involved in
the differentiation and maintenance of CTL, Th1 cells, memory CD8 T cells, as well as NK cells (45–49). In addition, epigenetic modifications such as demethylation and histone
acetylation have been observed in the Il2 and Ifng locus of
memory CD8 T cells, primary NK cells (50). The parallel expression of transcription factors, post-transcriptional mechanisms and epigenetic modifications could therefore provide
common molecular bases for the rapid and vigorous response of NK and memory CD8 T cells upon stimulation.
Cell proliferation
Like T and B cells, and in contrast to other innate immune cell lineages, it now well demonstrated that NK cells are also endowed
with great proliferative potential in situations of viral infections as
well as in lymphopenic conditions. Upon MCMV or vesicular stomatitis virus (VSV) infections, a ‘non-specific’ proliferation of NK
cells rapidly occurs, presumably driven by cytokines and reminiscent of the bystander proliferation of memory CD8 T cells
(50). This initial phase of cell proliferation is followed by a phase
of NK cell proliferation and significant expansion that appears
to be ‘antigen-specific’ and relies on the triggering of NK cellactivating receptors (50). During MCMV infection, the interaction between the MCMV m157 protein and Ly49H (as mentioned previously) leads to the activation, proliferation and
preferential expansion of the Ly49H+ NK cell population (50).
Similarly, VSV infection is associated with the preferential
expansion of a subset of Ly49H NK cells, suggesting that
VSV-derived proteins could also interact with NK cells through
specific NK cell-activating receptors (50).
Strikingly, whereas Ly49H+ NK cells undergo a roughly
10-fold expansion in the liver during MCMV infection of wildtype mice, this expansion can reach 100- to 1000-fold when
the initial frequency of Ly49H+ NK cells is experimentally decreased (51). Therefore, although significant and mimicking
the antigen-specific clonal expansion of T cells during an immune response, the NK cell proliferative potential appears to
be limited by stringent homeostatic constraints that remain
to be identified.
Cell-intrinsic role of NK cells in adaptive immune
responses
Considering the many developmental, functional, phenotypic
and genetic similarities between NK cells and T cells, one
very intriguing question was whether NK cells could also
have the cell-intrinsic ability to mediate adaptive immune
responses, i.e. recall or memory responses.
A first answer to this question came from seminal studies
showing that a subset of liver NK cells was able to mediate
the prototypical adaptive immune response of contact hypersensitivity to haptens as well as virus-derived proteins in
430 NK and T cell relationships
mice lacking T and B cells (52, 53). NK cells isolated from
Rag /
mice
sensitized
with
dinitrofluorobenzene,
oxazolone, influenza, VSV or HIV-derived proteins and adoptively transferred into naive Rag / Il2rg / mice (lacking
T, B and NK cells) confer sensitivity to subsequent challenge
with the sensitizing agents as well as increased protection
against viral infection, up to 4 months after transfer (52, 53).
These results demonstrated that subpopulations of hepatic and pulmonary NK cells possess the intrinsic ability to
transfer long-lasting and highly specific immunity to a naive
host, a feature only ascribed so far to adaptive immune
cells, i.e. T and B cells. Also, as previously mentioned, when
transferred into DAP12-deficient mice (defective in Ly49H
expression and function), Ly49H+ wild-type NK cells are able
to mount a typical adaptive immune response directed
against the m157 MCMV protein, including a significant
‘clonal’ expansion followed by a contraction phase (50, 51).
Moreover, subsequent viral-challenge experiments have
revealed that several weeks later the remaining ‘activationexperienced’ NK cells are able to mount a secondary
response with similar kinetics to the primary one but with
enhanced effector functions (51). In agreement with these
observations, NK cells activated in vitro with a combination
of IL-12 and IL-18 and ‘parked’ in vivo also proliferate and
display an enhanced ability to secrete IFN-c, regardless of
the numbers of cell division, up to 3 weeks later (43).
Altogether these studies demonstrate that NK cells have
the intrinsic ability to retain an enhanced effector potential
along time and upon cell division and support the idea that
similar to T cells (and B cells), NK cell activation during an
immune response can generate memory NK cells.
Concluding remarks
Despite the initial description of NK cells as ‘bona fide’ innate immune cells, recent evidence indicates that this classification might not be as clear as expected. Several genetic,
phenotypic, developmental and functional studies support
the idea that NK cells are related to T cells, culminating with
the recent descriptions of cell-intrinsic memory-like features
of NK cells. Notably, these last discoveries should also
prompt research aiming to re-evaluate the existence of potential adaptive immune features displayed by other innate
immune cell types such as macrophages (40).
However, before refining the whole concepts of innate and
adaptive immunity, it seems important to address some critical issues. Indeed, in sharp contrast with adaptive immune
cells, innate immune-cell lineages are characterized
by a very rapid turnover of their peripheral pool of effector
cells (;15 days for NK cells). Studies on ‘memory-like’
NK cells have been mostly carried out in settings where only
the ‘activation-experienced’ cells were able to respond to
further stimulation. One can therefore wonder whether these
memory-like NK cells are not rapidly diluted by the rapid
and constant input of newly produced NK cells in normal
physiological settings. Whether the presence of a minute
fraction of memory NK cells in a whole NK cell population
able to respond to a specific stimulation does make
a difference in terms of immune memory efficiency, therefore
represents a critical question that has to be addressed.
Funding
Association pour la Recherche sur Cancer to E.N.M.; Fondation pour la Recherche Médicale to Y.M.K.; The laboratory of
E.V. is supported by the Ligue Nationale contre le Cancer
(équipe labélisée), INSERM, CNRS, Université de la Méditerranée, Institut Universitaire de France and an ERC advanced
Grant
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