(NK) Cells in Antibacterial Innate Immunity

16 Pages·2012·0.91 MB·English

Natural Killer (NK) Cells in Antibacterial Innate Immunity:
Angels or Devils?
Fernando Souza-Fonseca-Guimaraes, Minou Adib-Conquy, and Jean-Marc Cavaillon
Institut Pasteur, Cytokines and Inflammation Unit, Department of Infection and Epidemiology, Paris, France
Natural killer (NK) cells were first described as immune leukocytes that could kill tumor cells and soon after were reported to kill
virus-infected cells. In the mid-1980s, 10 years after their discovery, NK cells were also demonstrated to contribute to the fight
against bacterial infection, particularly because of crosstalk with other leukocytes. A wide variety of immune cells are now rec-
ognized to interact with NK cells through the production of cytokines such as interleukin (IL)-2, IL-12, IL-15 and IL-18, which boost
NK cell activities. The recent demonstration that NK cells express pattern recognition receptors, namely Toll-like and nucleotide
oligomerization domain (NOD)-like receptors, led to the understanding that these cells are not only under the control of acces-
sory cells, but can be directly involved in the antibacterial response thanks to their capacity to recognize pathogen-associated
molecular patterns. Interferon (IFN)-γis the predominant cytokine produced by activated NK cells. IFN-γis a key contributor to an-
tibacterial immune defense. However, in synergy with other inflammatory cytokines, IFN-γcan also lead to deleterious effects sim-
ilar to those observed during sepsis. Accordingly, as the main source of IFN-γin the early phase of infection, NK cells display both
beneficial and deleterious effects, depending on the circumstances.
Online address: http://www.molmed.org
doi: 10.2119/molmed.2011.00201
ANTIBACTERIAL INNATE IMMUNITY ride [LPS]), the lipoteichoic acid of gram- like receptors (NLRs) has led to an un-
Microbial invasion into sterile body positive bacteria and many other compo- derstanding of the interaction between
compartments causes infectious diseases nents (for example, lipoproteins, outer- microorganisms and hosts, as well as the
that are locally addressed by cells of the membrane proteins, flagellin, fimbriae very early steps of the innate immune re-
innate immune system (1). Although ac- and peptidoglycan). In addition, bacter- sponse. TLRs are expressed either on the
tors of humoral immunity such as natu- ial lysis results in the release of internal cell surface (TLR1, -2, -4, -5 and -6) or
ral antibodies, pentraxins and factors of motifs (for example, heat-shock proteins, within endosomes (TLR3, -7, -8 and -9).
the complement system contribute to RNA, and DNA fragments), which are NLRs are cytoplasmic sensors. In addi-
fight microbes in the early steps of innate additional PAMPs recognized by im- tion to cytokine production, the interac-
immune response, cellular immunity mune cells. These cells express pattern tion of different PAMPs with their re-
does play a key role (2). As sensors of recognition receptors (PRRs), specifically spective TLRs or NLRs initiates
pathogenic microbial agents, innate im- recognizing PAMPs. The activation of numerous intracellular signaling path-
mune cells recognize microbial-associated PRRs initiates the innate immune antiin- ways that result in the activation of im-
or pathogen-associated molecular pat- fectious response and the early produc- mune and inflammatory genes, including
terns (PAMPs) by intracellular or cell tion of cytokines, which orchestrate this costimulatory molecules, adhesion mole-
surface receptors. PAMPs are microbial response (3). Among PRRs, the discovery cules and antimicrobial mediators (2,4,5).
molecules such as the endotoxin of of Toll-like receptors (TLRs) and nu- After infection, after PAMP recogni-
gram-negative bacteria (lipopolysaccha- cleotide oligomerization domain (NOD)- tion by immune cells, there are two well-
characterized steps of the immune re-
sponse illustrated by the production of
Address correspondence toJean-Marc Cavaillon, Institut Pasteur, Unité Cytokines & pro- and antiinflammatory cytokines. In
Inflammation, Départment Infection et Epidemiology, 28 rue du Docteur Roux, F-75015 the most severe cases of infection (e.g.,
Paris, France. Phone: [phone]; Fax: [phone]; E-mail: during sepsis), an overzealous release of
[email protected]. proinflammatory cytokines and inflam-
Submitted June 8, 2011; Accepted for publication November 9, 2011; Epub matory mediators by activated leuko-
(www.molmed.org) ahead of print November 10, 2011. cytes, epithelial cells and endothelial
cells, known as a “cytokine storm,”
leads to deleterious effects such as organ
dysfunction and even death. Almost
270 | SOUZA-FONSECA-GUIMARAES ET AL. | MOL MED 18:270-285, 2012
REVIEW ARTICLE
concomitantly, this proinflammatory re- NK cells in bacterial infection. The lack compartments. Most parameters of
sponse is accompanied by the release of of natural antibacterial activity against human NK cells have been acquired
antiinflammatory cytokines and neuro- Salmonella typhimuriumof beige mice, from cells derived from the blood com-
mediators aimed to dampen the inflam- known to be deficient in NK activity, was partment, whereas murine NK cells are
matory process. The side effect of this not recognized as evidence supporting mostly derived from spleen. It is interest-
antiinflammatory response is the alter- the role of NK effector cells in natural an- ing to note that the blood environment in
ation of immune status known as the tibacterial activity (17). The first report mice and humans are greatly different,
“compensatory antiinflammatory re- on the role of NK cells during bacterial with murine plasma favoring the re-
sponse syndrome” (6), favoring the oc- infection was related to their capacity to silience of mice to bacterial infection (27).
currence of nosocomial infections (7,8). lyse either Shigella flexneri–infected HeLa
The early cellular immune response in- cells (18), Legionella pneumophila– infected BACTERIAL SENSING BY NK CELLS AND
volves the contribution of mast cells, monocytes (19) or Mycobacterium EXPRESSION OF PRRS
mononuclear phagocytes and polymor- avium–infected monocytes (20). The latter A large part of the knowledge on TLR
phonuclear phagocytes (9). More re- study also reported that NK cells could expression in human NK cells was ini-
cently, it became evident that natural help macrophages to inhibit growth or tially acquired in studies on the basis of
killer (NK) cells were also key players in kill intracellular bacilli (21). Similar find- mRNA detection. In human NK cells, di-
early immunity (10). The fact that TLRs ings were reported for Mycobacterium lep- vergent observations were reported. In
were recently discovered to be expressed raemurium (22). The key in vivorole of pooled purified NK T cell–like (NKT
by NK cells has opened a new interest NK cells during a bacterial infection was cell–like) and NK cells (CD3+CD56+and
for their putative involvement in innate initially established in M. aviuminfec- NK CD3–CD56+, respectively), the ex-
immune response to bacterial infections. tion: an in vivodepletion of NK activity pression of all TLR mRNA (TLR1–9) was
It seems that in contrast to phagocytes, using antibodies provided direct evi- found (28), but in isolated NK cells,
the activation of NK cells by PAMPs can dence on their role in the control of intra- mRNA expression levels of TLR1 were
only occur within a complex crosstalk cellular mycobacterial pathogens (23). highest, followed by moderate levels of
with other immune cells that offer the Since then, the role of NK cells in bacter- TLR2, TLR3, TLR5 and TLR6 (29). One
cytokine microenvironment required for ial infection has been clearly established, group demonstrated a lack of TLR9
NK cell responsiveness (11). Accord- including the cytokine microenviron- mRNA expression in two different sorted
ingly, similar to any other cellular or ment and the cellular crosstalks required populations (NKT cell–like CD3+CD56+,
molecular participant in infectious dis- for an active contribution of these cells in NK CD3–CD56dimand NK
eases, NK cells can play an “angel” or innate antibacterial immunity (Figure 1). CD3–CD56bright) (10). Regarding murine
“devil” role, depending on the circum- It is possible that all NK cell subsets NK cells, divergences in mRNA expres-
stances. The same actors, which con- are not equivalent in their antibacterial sion were also reported. One study re-
tribute to fight infection, can act in syn- activity. However, human and mouse ported that all TLR mRNAs were ex-
ergy, leading to acute deleterious NK cell subsets will not be detailed in pressed in splenic murine NK cells (30),
inflammation. This is particularly the this review (for detailed reviews about whereas in the other, only TLR2, TLR4,
case of γ-interferon (IFN-γ), which is one NK cell subsets, see Huntington et al.[24] TLR8 and TLR9 were found, but not
of the main cytokines produced by NK and Wilk et al.[25]). For example, it has TLR3 and TLR7 (31).
cells (12). been shown that in response to BCG Of course mRNA expression is not al-
The concept of NK cells was first re- (bacillus Calmette-Guérin), human ways a reflection of the protein expres-
ported in 1975 by Hans Wigzell’s group, CD56BRIGHTNK cells were cells mainly sion, because of posttranscriptional,
which established that leukemia cell involved in IFN-γproduction, whereas translational and posttranslational
lines could be lysed by cells with the the CD56DIMsubset contained higher lev- events. Furthermore, cellular localization
morphology of small lymphocytes and els of perforin and granzyme A (26). In may also influence the cell surface ex-
devoid of T- and B-cell characteristics addition, NK cell differentiation and pression. Studying human uterine NK
(13). Their expression of Fcγreceptors function are influenced by tissue envi- cells, Eriksson etal.(32) showed that
(14), and their capacity to kill target cells ronment. Specific cellular and molecular TLR2 was not localized on the cell sur-
through antibody-dependent cell cyto- environments in the uterus, liver, spleen, face but was expressed intracellularly.
toxicity, was demonstrated thereafter lungs or blood influence the precise na- For circulating human NK cells, the sur-
(15). Soon after, it was reported that NK ture of NK cells. Furthermore, differ- face expression of this receptor remains
cells were also active against virus-in- ences have been noticed between species. controversial. Flo etal.(33) failed to de-
fected cells (16), opening a new field of However, it should be mentioned that tect TLR2 expression by flow cytometry
investigation to be explored. In contrast, most studied human and murine NK on a freshly isolated human NK cell sur-
it took more time to accept the role of cells are generally derived from different face using two different monoclonal anti-
MOL MED 18:270-285, 2012 | SOUZA-FONSECA-GUIMARAES ET AL. | 271
NK CELLS IN BACTERIAL INFECTION
bodies. In contrast, Becker etal.(34)
showed that after 24 h of culture, puri-
fied NK cells displayed TLR2 surface ex-
pression, as revealed by staining with a
polyclonal antibody. Interestingly, TLR3
expression by human NK cells was
shown to be expressed both on the cell
surface (35) and intracellularly (36).
TLR9 was found either in all human
blood NK cells (36) or only in a small
subpopulation, of which the percent
could be increased after yellow fever
vaccination (37). Concerning mouse
spleen NK, a recent study showed that
cell surface expression of TLR2 was pres-
ent on ~65% of negatively selected
freshly isolated NK cells and was not sig-
nificantly modified after 48 h of culture
in the presence of IL-2 and IFN-αwith or
without the Vacciniavirus (31).
The presence of any TLRs can be
demonstrated indirectly by the activation
of NK cells by TLR agonists (Table 1).
Figure 1.Activation of NK cells by bacterial PAMPs. NK cells are activated within a network
For example, flagellin, the ligand of
of accessory cells that sense bacterial PAMPs. Activation of accessory cells leads to the
TLR5, favors NK cell recruitment in
production of cytokines that contribute to the functional activation of NK cells, while sens-
lymph nodes, upregulates CD69 expres- ing of PAMPs by NK cells themselves further enhances NK cell reactivity. All listed cytokines
sion on NK cells and induces NK-cell have been shown to amplify NK cell activity, either alone or in synergy. Negative signals
proliferation and IFN-γproduction (38). can be directly delivered to NK cells (for example, IL-10 and TGF-βproduced by Tregs,
In contrast, flagellin abrogates prostaglandins or glucocorticoids) or indirectly by downregulating the function of acces-
cytosine–phosphate–guanine (CpG) sory cells. PGN, peptidoglycan; OmpA, outer-membrane protein A, MØ, macrophages;
oligonucleotide-induced cytolytic activ- PMN, polymorphonuclear leukocytes (neutrophils); B, B lympocytes; MAST, mast cell; EPITH.,
epithelial cell; PGE, prostaglandin E ; PGD, prostaglandin D.
ity of NK cells (39). However, CpG 2 2 2 2
oligonucleotide, a TLR9 ligand, failed to
directly activate isolated NK cells (28,29) glioside (GM1) antibody depletes NK ramyl tripeptide (mur-tri-DAP), more
because most of these activations are ac- cells and basophils (43). Thus, the pu- frequently found among gram-negative
cessory cells and/or accessory cytokine- rification method (and possible cellular bacteria. NOD2 is a receptor for mu-
dependent (see below). activation) may indeed contribute to the ramyl dipeptide (MDP), the smallest ac-
The method for NK cell purification is controversial reports published when tive part of peptidoglycans from both
a technical limitation that can explain studying the expression of TLRs in NK gram-negative and gram-positive bacte-
some of the controversial observations. cells. Furthermore, analysis performed ria. NLRP3 is a key member of the in-
Often used, the positive selection with either extemporaneously or after cell flammasome and a sensor for many toxic
magnetic microbeads may either induce culture can also lead to divergent re- agents. Human NK cells express high
cellular activation and modification of sults. levels of intracellular NOD2, and
cell surface marker expression (40) or be Others PRRs have been expressed by NLRP3, whereas NOD1 is expressed at
associated with the presence of contami- NK cells, including the families of cyto- very low levels (36). Human NK cells
nating dendritic cells (41). Divergent re- plasmic sensors, the NOD-like receptors naturally internalize MDP, which to-
sults are similarly obtained in vivode- (NLRs) and the retinoic acid inducible gether with IFN-αand IL-12 stimulate
pending on the antibody used for NK gene I (RIG-I)-like receptors. NLRs in- the secretion of IFN-γ(44). Studies on the
cell depletion (42). For example, in vivo clude NOD1, NOD2 and NOD-like re- activation of NK cells by synthetic dou-
cell depletion with anti-NK1.1 antibod- ceptor family, pyrin domain containing 3 ble-strand RNA (poly I:C) led to the con-
ies leads to the elimination of both NK (NLRP3). NOD1 is a receptor for small clusion that RIG-I–like receptor expres-
and NKT cells, whereas the use of the motifs derived from peptidoglycan, such sion but not TLR3 was involved in NK
anti–asialo monosialotetrahexosylgan- as diaminopimelic acid-containing mu- cell activation (45). The use of mice defi-
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a d
7 9 e
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Nature of NK cell activation γCytotoxicity, IFN- production Cytotoxicity CD25 and CD69 expression, γIFN-production γFN-production γFN-production γFN-production γFN-production γFN-production CD25 and CD69 γexpression, IFN- production, proliferation CD69 expression Cytotoxicity, CXCL10 γand IFN-production γαFN-and -defensin production CD69 and CD25 expression, cytotoxity, γIFN-and TNF production γFN-production γFN-production γCD69 expression, IFN- production proliferation γFN-production γFN-production and cytotoxity Cytotoxicity γFN-production and cytotoxity
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Table 1.Response of NK cells to Bacteria or bacterial PAMPs Legionella pneumophila LPS S. aureus L. monocytogenes Mycobacterium bovis BCG E. coli DNA E. coli DNA LPS E. coli, Lactobacillus CgG oligonucleotide Poly(I:C) K. pneumoniaeOmpA, flagellin Poly(I:C) and CpG L. monocytogenes H. pylori lysates Flagellin Secreted mycobacterial (proteins ESAT-6 and MPP14) Peptidoglycan, poly(I:C) LPS, flag Lactobacillus casei Poly(I:C), loxoribine
MOL MED 18:270-285, 2012 | SOUZA-FONSECA-GUIMARAES ET AL. | 273
NK CELLS IN BACTERIAL INFECTION
0 cient for MDA5 (another member of the
Sawaki etal.Int. Immunol.2007, 19, 311 Schierloh etal.Infect. Immun.2007, 75, 5325 Marcenaro etal.Int. Immunol.2008, 20, 1155 Athie-Morales etal.J. Immunol.2010, 185, 208 Elkins etal. Microbes Infect.2009, 11, 49 Perrot etal.J. Immunol.2010, 185, 1379 Mian etal.Mol. Ther.2010, 18, 1379 Lindgren etal.Innate Immun.2010, 17, 191 Azuma etal.PLoS One.2010, 5, e12550 Cheon etal.Immunol. Lett.2011, 136, 171 acytoid dendritic cells; APC, antigen umber. Rlapccict1tnAunhhuoan9arI vleenon(8IGldmaSnem o2m csr -d P etl,l toIa vhusori–dEwafdreeeaslt r Aeitnpeddsietekcho tr s)t i oters enk oitolselnfih y nca rort Mpt om io etohanamotewccDcwoac,ifrec ccu ,tcttepa Adniee oowldvtlts oa xhc5 doaa seatucfi isootrenrpossabe yfrr srsfal iapl-y at N ucet1ptbrha mhi-hpe ceylKrts(weeleheonaitre llr ronwgctatylafaa soieg,e ysfnr n aa loneea()sildydt4,dnnrst ii k c6e a.lgid wti e cebd,pSinet4udm yoyao ntte7Rc oe sx mxste)iebr roNni..o m f n atei ItmethtnAc,nr oarh otaa rooxi)evefectn,nlirie-envli-lya-o-
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γFN-production and cytotoxity γFN-production CD69 and CD25 γexpression, IFN-and TNF production CD69 expression, γIFN-production Control of intracellular bacterial growth γFN-production and cytotoxity CD69 expression, cytotoxity and γIFN-production γFN-production γFN-production and cytotoxity Cytotoxicity and granule exocytosis acrophages; pDC, plas es the beginning page tpcfestahouhincortirtotcrositetwuv hxretaloeoideactrxtdte oiaiic nnnxNtcoh g itn1wnKia v9fI t iiFB9i ctrtSN1h meyiP .l sb- NleE Tγsayd AKhn(a S4e (no i85ac ndtce)0chca. lk) ielrp.Tnss erSa hd aewstcetsuaui eatapcfpydsileh.re posyNrI(tF4arfl oKo9NnlSib)ctn P,-ocia γkgEwecb elwAcollhnay f caolt yrsoe--
mI hI h h m hI m and h hI mI h cytes or mm, murine.ber indicat arloibfciloeed ctc oNa li Kned ncuteeclrleso tt(ho5ex1 i)rn.e IlBne,a cssoteun odtrfi aeIssFt N stuo-gγ sgbtaeysp tphuy--
onon; um that NK cells were not directly activated
TLR2, -3 and -7IL-12 TLR2 + TLR4IL-12 + APC contact TLR2± IL-12 αNOD2IL-12 or IFN- TLR9Infected MØ αRIG-like receptor IL-12 and IFN-not TLR3 TLR4 agonistIL-2 TLR2IL-12 TLR2+ BMDC contact NDPBMC peripheral blood mononuclear cells; MØ, mw derived dendritic cells; b, bovine; h, humance citation indicates the volume; the last n cblaeowttNa(Ptooio5onnnfysvgKa4cl nevdd yNaeos)su tin.t t tccr rdmIKeriaTeecaoLceo sp al ishnopm-cvlnltht1senmeo ,hi o 8e yr vlotrinaelu nehniltspcxtvoaenltr ysreooevd(ciot on5tnroit a ueNtro2odfdccerseog,xtrecouuK 5qorhucia c3c nfsu xo gllacee)tti iini.hueesAcddnrn tAttlneed oe lroAbId p t isirFscresbyea ir–t yNifrosoo ui maoowmmt lfdt-oocyrt eγioaLt uautnslt ioaspxicithvclsno pxarrierasetno tioeedho tOtci rpardehoA iobiibc,tdhanuep wsyt.ay a e icmh cTbS vng(trcye5iyt voa eyocartt5n tasoe-aoInpi)otLolkl. hilc abno-siIyy1cnnyn---2e
bine) man marroefere baelrouogdi nmosoaneoxneurtcsl eaanr icnehllisb riteovreya laecdti othna ot nP.
Table 1.Continued. Peptidoglycan, poly(I:C) (loxori M. tuberculosis M. bovis MDP CgG oligonucleotide Poly(I:C) E. coliFimbriae FimH H. pylori(HpaA lipoprotein) Diacyl lipopeptide Lactobacillus acidophilus ND, not determined; PBMC, hupresenting cells; BMDC, bone aThe second number in each r aisgttmrNmhoeoniyKegxemIdmcsfsiu ne eceNcltut e a oeypcpnlKmt telirlaeosoil oct m,cltnod hdsoepm. eoiulx ortlTfgii ecsfetcth eevahnicadnitneeesrsysn sele b al i, t,( h sk yciw5si nateu tt6iAh vhgy)orm.e eifc nIcaa t aFcd hiccaknNate enieoos vn-bmsedrγeh as sola capioeobifrcrlnp fkitlot tuisehtesdvehsdre au tse athtlsch cieitetotanuri inoatunnktn opaooe-t---fe
274 | SOUZA-FONSECA-GUIMARAES ET AL. | MOL MED 18:270-285, 2012
REVIEW ARTICLE
associated with NK cell activation (57). achieved similarly. The release of cyto- neutralization of IFN-γprevented lethal-
More drastically was the case of Yersinia toxic molecules is polarized toward a tar- ity in primate gram-negative bacteriemic
pestis, in which the yersinial outer mem- get cell, whereas that of cytokines is not shock(90) and protected miceinfected
brane protein-11 (YopM) molecule, a (62). NK cells can be rapidly activated by intravenously with Staphylococcus aureus
41.5-kDa virulence protein, interferes some of the cytokines present in the early (91). The deleterious role of IFN-γwas
with innate immunity by causing a stages of infection, such as IL-12, IL-15 or demonstrated by its capacity to increase
global depletion of NK cells, possibly by IL-18, allowing the secretion of large death when injected in mice, particularly
affecting the expression of IL-15 receptor amounts of IFN-γand GM-CSF. NK cells when acting in synergy with TNF-α(12).
αand IL-15 (58). also generate other cytokines such as IL-5 This deleterious effect was also shown in
(63), IL-6 (64), IL-10 (65,66), transforming the CLP model of polymicrobial peritoni-
NK CELLS AS A SOURCE OF growth factor (TGF)-β(67), IL-12 (68), IL- tis(92) and in a CLP model followed by
INFLAMMATORY CYTOKINES AND 13 (69), IL-16 (25), IL-17 (70) and IL-22 a P. aeruginosainfection(93).Polymicro-
ANTIMICROBIAL MEDIATORS (71). Similarly, NK cells are source of var- bial peritonitis performed in IFN-γ
NK cells produce cytokines that con- ious chemokines such as XCL1, CCL1, receptor–deficient mice(94)or in rats
tribute to the inflammatory environment CCL2 and CXCL16 (72); CXCL8, CCL8, given anti–IFN-γantibodies(95) led to
during an infection. IFN-γ, granulocyte- CCL26 and CCL17 (25); CXCL10 (73); the similar demonstration of this nega-
macrophage colony-stimulating factor CCL3 and CCL4 (74); and CCL5 (75). NK tive role. In mice injected with LPS, the
(GM-CSF), and tumor necrosis factor cells also release soluble TNF-α(76) and ambiguous role of IFN-γwas demon-
(TNF)-αare the main cytokines gener- express its membrane form (77), as well strated: IFN-γprotected against LPS-
ated by activated NK cells (24,59). For as other members of the TNF family (that induced lung edema but acted in syn-
example, in the cecal ligation and punc- is, lymphotoxin [LT]-α, LT-β, Fas ligand, ergy with LPS to enhance the occurrence
ture (CLP) model of polymicrobial peri- CD27L, CD30L, OX40L, 4-1BB ligand of death (96).
tonitis, it was established that liver NK (4-1BBL), TNF-related apoptosis-inducing NK cells were also recognized as a
cells were the main source of IFN-γ(60). ligand (TRAIL) and LIGHT (homologous source of α-defensins and cathelicidin
Whether these cytokine productions are to lymphotoxins, exhibits inducible ex- (LL37), well-known antibacterial pep-
accessory cell–dependent remains a con- pression, competes with HSV glycopro- tides (97). NK cells can also generate in-
troversial issue. Nonetheless, there are tein D for HVEM, a receptor expressed doleamine 2,3-dioxygenase (IDO) and ni-
numerous reports showing that purified on T-lymphocytes) (72,78). tric oxide (NO), two other mediators
NK cells can directly respond to PAMPs The fact that NK cells are an important known to limit the infectious process
in the absence of accessory cells, but in source of proinflammatory cytokines, (98,99). So far, the generation of IDO by
the presence of cytokines such as IL-2, particularly IFN-γ, illustrates how these NK cells has not been demonstrated in
IL-12, IL-15 or IL-18 (see Table 1). cells are both contributing to the antiin- the context of bacterial infection, but has
Whereas most cytokines are undetect- fectious process and amplifying the in- been in a transplantation model after
able in the bloodstream of healthy sub- flammatory response that can lead to IL-4 treatment (100). Similarly, the pro-
jects during homeostasis, there is a low organ failure and death, as seen in duction of NO has not been demon-
and different expression in various tis- polymicrobial sepsis. NK cells have been strated in infectious models, but rather in
sues. This expression creates a microen- identified in numerous studies as the response to IL-2 (101), IL-12 and TNF-α
vironment that modulates the precise main source of IFN-γduring infection by (102). In both cases, the authors showed
nature of different NK cells. During in- different bacterial pathogens such as activation of inducible NO synthase. In
fection and sepsis, a large panel of cy- Francisella tularensis (79), L. monocytogenes addition, NK cells express endothelial
tokines is generated, offering NK cells (80–82), Chlamydia pneumoniae(83), and NO synthase and thus can constitutively
the appropriate environment to respond Yersinia enterocolitica(84) and in experi- produce NO (103). Most interestingly, it
to PAMPs, allowing contribution to the mental endotoxin-induced lethal shock was recently shown that NK cells can
cytokine cascade and eventually to the (85) and polymicrobial sepsis (86) (Tables 1 also be a source of resolvin E1, suggest-
cytokine storm (1,61). and 2). The protective role of IFN-γwas ing that they can also contribute to the
Activation of NK cells can lead to dif- shown in murine salmonellosis, particu- resolution phase of inflammation (104).
ferent changes including cytotoxity asso- larly in synergy with TNF-αwhen in-
ciated with the release of perforin and jected 6 h before S. typhimurium(87). This NK CELLS AND ACCESSORY
granzyme and the production of cy- beneficial role was also demonstrated in CYTOKINES
tokines. The secretion of cellular granules IFN-γreceptor–deficient mice, which Despite the fact that NK cells are
containing cytotoxic mediators (for exam- were more sensitive to group B Strepto- equipped to recognize bacterial patterns,
ple, perforin and granzyme) and cy- coccus (88)or to ascendens stent peritoni- it is well established that accessory cells
tokines (for example, IFN-γ) are not tis (89) than wild-type mice. In contrast, contribute both indirectly (through
MOL MED 18:270-285, 2012 | SOUZA-FONSECA-GUIMARAES ET AL. | 275
NK CELLS IN BACTERIAL INFECTION
Table 2.Some examples of cellular crosstalk allowing NK cell response during bacterial infections or PAMP challenge.
Cellular crosstalk with NK cells and type of
infection or activation NK cell functions References
Dentritic cells
LPS Proliferation, cytotoxicity, Goodier etal.J. Immunol.2000, 165, 139a
IFN-γproduction
LPS or M. tuberculosis CD69 expression, Gerosa etal.J. Exp. Med.2002, 195, 327
IFN-γproduction
TLR3, -4, -7 and -9 agonists IFN-γproduction and cytotoxicity Lucas etal.Immunity.2007, 26, 503
L. monocytogenes IFN-γproduction Lucas etal.Immunity.2007, 26, 503; Kang etal.
Immunity.2008, 29, 819; Humann and Lenz.
J. Immunol.2010, 184, 5172
Pam2Cys lipopeptides CD69 expression, cytotoxicity Azuma etal.PLoS One.2010, 5, e12550
and IFN-γproduction
Chlamydia muridarum IFN-γproduction Jiao etal.J. Immunol.2011, 187, 401
Monocytes/macrophages
CpG DNA IFN-γproduction Chace etal.Clin. Immun. Immunopathol.1997, 84, 185
Legionella pneumophila IFN-γproduction and cytotoxicity Blanchard etal.Infect. Immun., 1988, 56, 1187
L. monocytogenes IFN-γproduction Wherry etal.Infect. Immun.1991, 59, 1709; Tripp et
al.PNAS.1993, 90, 3725
P. aeruginosa exotoxin A IFN-γproduction and cytotoxicity Michalkiewicz etal., Immunol. Lett.1999, 69, 359
S. aureus; L. johnsonii CD69 expression, Haller etal.Clin. Diag. Lab. Immun.2002, 9, 649
IFN-γproduction
LPS CD69 expression Scott etal.Clin. Exp. Immunol.2004, 137, 469
TLR2, -3 and -4 agonists IFN-γproduction Tu etal.J. Exp. Med.2008, 205, 233
Salmonella CD69 expression, cytotoxicity Lapaque etal.J. Immunol.2009, 182, 4339
and IFN-γ
Kupffer cells
TLR2, -3 and -4 agonists IFN-γproduction Tu etal.J. Exp. Med.2008, 205, 233
Poly I:C + D-GalN in vivo IFN-γproduction Hou etal.Hepatology.2009, 49, 940
Neutrophils
Legionella IFN-γproduction Sporri etal., J. Immunol.2008, 181, 7121
LPS + IL-2 or IL-15/IL-18 IFN-γproduction Costantini etal.Blood.2011, 117, 1677
T-lymphocytes
Staphylococcal enterotoxin B–activated T cells IFN-γproduction and cytotoxicity D’Orazio etal.J. Immunol.1995, 154, 1014
LPS-treated γδT cells IFN-γproduction Andrews etal.Immunol. Cell. Biol.2011, 89, 739
B-lymphocytes
L. monocytogenes IFN-γproduction Bao etal.Eur. J. Immunol.2011, 41, 657
Mast cells
LPS, Poly(I:C), CpG IFN-γproduction Vosskuhl etal.J. Immunol.2010, 119, 25
Epithelial cells
Chlamydia trachomatis IFN-γproduction Hook etal.FEMSImmunol. Med. Microb.2005, 45, 113
aThe second number in each reference citation indicates the volume; the last number indicates the beginning page number.
soluble factors) and directly (through to amplify the survival, the proliferation, tion, normal T-cell expressed and [pre-
cell-to-cell contact) to trigger the cellular the IFN-γproduction or the cytotoxicity sumably] secreted [RANTES]), CCL7
response. Several studies have demon- of NK cells. This is the case for TNF-α (MCP-3), CCL8 (MCP-2) and CXCL10
strated the NK cell activation by TLR ag- (107), IL-4 (100,108), IL-1β(109), IL-7 (71), (interferon γ–induced protein [IP]-10) (112).
onists can occur in the absence of acces- IL-23 (110) and IL-33 (111). NK cells re- In the case of CCL6 (C10), transgenic
sory cells but in the presence of their spond to chemoattractant signals deliv- mice overexpressing this chemokine
soluble cytokines. IL-2, IFN-α/β, IL-12, ered by numerous chemokines, particu- were shown to be protected against an
IL-15, IL-18 and IL-21 are the main cy- larly CCL2 (macrophage-chemoattractant otherwise lethal CLP, associated with an
tokines that trigger NK cells, either alone protein [MCP]-1), CCL3 (macrophage in- enhanced recruitment of NK cells in the
or in a synergistic combination (105,106). flammatory protein [MIP]-1α), CCL4 peritoneal cavity (113). Furthermore,
Other cytokines have also been reported (MIP-1β), CCL5 (regulated upon activa- these chemokines enhance the cytolytic
276 | SOUZA-FONSECA-GUIMARAES ET AL. | MOL MED 18:270-285, 2012
REVIEW ARTICLE
response of NK cells. Whereas IL-15 is ble KO mice and combined experiments and B and T lymphocytes, including reg-
the prerequisite cytokine for NK cell with anti–IL-12 and anti–IL-18 antibod- ulatory T-cells (Tregs) (see Table 2).
maturation and differentiation from ies demonstrated that both IL-12 and IL- In vitroproduction of IFN-γby spleen
bone marrow cells (114), it is also re- 18 cooperate to activate NK cells cells stimulated with S. typhimurium re-
quired for an optimal IFN-γproduction (127,129). A recent report showed that quires the help of adherent cells or ad-
(115). Interestingly, IL-15 can be deliv- IL-18 primes NK cells to become respon- herent cell-derived factors (146). In this
ered to NK cells in a trans- presentation sive to IL-12 and to release IFN-γ(130). early study, NK cells were not identified
manner (116,117). IL-15 and IL-2 share a A coordinated action with other cy- as a source of IFN-γ, and adherent cells
common receptor chain (IL-2Rβ) (118), tokines such as IFN-α/βhas been could have been either DCs or
and NK cells are also responsive to IL-2 demonstrated during viral infection. macrophages, making this report among
(119). Such a responsiveness is not only TLR4 agonists can also generate the re- the first to demonstrate that a cellular
an illustration of the crosstalk between lease of IFN-α/β; it is most probable that crosstalk was required for IFN-γproduc-
NK cells and T lymphocytes, the main IFN-α/βalso contributes to the activa- tion. Since then, the requirement of ac-
source of IL-2, but also with dendritic tion of NK cells during bacterial infec- cessory cells for NK cell activation was
cells (DCs), which have been shown to tion (131). well documented (see Newman and
contribute to NK cell activation through Of course, NK cells are also responsive Riley [145] for a review). DCs were iden-
the release of IL-2 (120). IL-12 was recog- to antiinflammatory mediators such as tified as a key partner for NK cells, par-
nized as an important cytokine to fight IL-4 (106), IL-10 (132), TGF-β(133), ticularly because they are a major source
infectious diseases (121,122), particularly prostaglandin E (134,135), prostaglandin of IL-12 and can also produce IL-15,
2
through its capacity to induce IFN-γpro- D (136) and glucocorticoids (137,138). In IL-18 and IFN-α(11,147). For example,
2
duction, as shown in mice infected with mice, in vivoblocking of IL-10 reverted proliferation, cytotoxic activity and IFN-γ
Y. enterocolitica (84) or S. typhimurium the hyporesponsive status of NK cells in production by LPS-stimulated NK cells
(123). Salmonellawas also shown to in- the lungs or the liver (139,140). In pa- depended on major histocompatibility
duce the production of IL-1βand IL-23 tients with chronic hepatitis B virus infec- complex (MHC) class II+B7+CD14–ac-
by macrophages favoring the production tion, in ex vivoexperiments, blockade of cessory cells, most probably DCs (148).
of IFN-γby NK cells (124). A similar syn- IL-10 or TGF-βrestored the altered capac- Studying the response of NK cells to L.
ergy between IL-1βand IL-12 leading to ity of NK to produce IFN-γ(141). How- monocytogenes, it was demonstrated that
an enhanced production of IFN-γwas ever, IL-10 may not always be a direct in- both cytokines and cell contact with in-
also reported in response to LPS and L. hibitor for NK cells. Particularly, IL-10 fected DCs were required for optimal
monocytogenes(109). It is interesting to was shown to enhance IL-18–induced IFN-γproduction by NK cells (149).
note that in return, IFN-γcan favor the IFN-γproduction and IL-18– and CX3CL1 (fractalkine) expressed on ma-
production of IL-12, as shown during IL-12–induced NK cell cytotoxicity and ture DCs is another player in the
the activation of macrophages by My- proliferation (142,143). Such a paradoxi- synapses formed between DCs and NK
cobacterium bovis(125). Similarly, IL-18, cal effect of IL-10 was confirmed when cells (150). Such contact was visualized
known to contribute to the antiinfectious regulatory DCs were added to NK cells by clustering of DCs, not only with NK
response and neutralization during an (144). These cocultures led to enhanced cells, but also with granulocytes and
infection with Y. enterocoliticaor S. ty- NK cell–dependent cytotoxicity and IFN-γ monocytes/macrophages (151) and in-
phimurium, was shown to be deleterious production. When regulatory DCs were volved the priming of NK cells by IFN-
(126). This study suggested that the role derived from IL-10 KO mice, their ampli- α/βand a trans-presentation of IL-15
of IL-18 depends on its capacity to in- ficatory role was significantly lower. (147).
duce the production of IFN-γ. In IL- Although the contribution of mono-
18–deficient mice injected with Propioni- NK CELLS WITHIN A CELLULAR cytes was shown to counteract the ef-
bacterium acnes, IFN-γproduction in CROSSTALK fects of DCs (148), other reports demon-
response to LPS was markedly reduced The activation of NK cells in bacterial strated a positive effect of monocytes/
and NK cell activity was significantly infection has often been linked to a cellu- macrophages. For example, inLegionella
impaired (127). Interestingly, during in- lar crosstalk with accessory cells that al- pneumophilaorL. monocytogenes infec-
fection, MyD88-deficient NK cells fail to lows NK cell activation after direct inter- tion, macrophages favored the produc-
produce IFN-γ(128). Because MyD88 is a action or accessory and NK cells with tion of IFN-γby NK cells (152,153). In
signaling molecule shared by most TLR PAMPs (145). Several accessory cells vitro, the presence of macrophages was
and also by IL-18 receptor, it is conceiv- have been described as a source of acti- fundamental for the expression of CD69
able that its absence could affect both vating signals for NK cells, such as DCs, by NK cells in the presence of LPS (154).
pathways during an immune response polymorphonuclear neutrophils, Crosstalk between human NK cells and
to infection. The use of IL-12/IL-18 dou- macrophages, mast cells, epithelial cells macrophages infected with intracellular
MOL MED 18:270-285, 2012 | SOUZA-FONSECA-GUIMARAES ET AL. | 277
NK CELLS IN BACTERIAL INFECTION
Salmonellawas also demonstrated. These cells and bacterial clearance depends on duce IL-17A, which together with IL-18,
macrophage-activated NK cells caused the NKG2D ligand (163). contribute to the IFN-γproduction by
the secretion of IFN-γand degranula- Neutrophils are central players during NK cells (174). Tregs constitute another
tion. The NK cell activation required the innate immunity against infection. Their T-cell subtype characterized as
release of IL-2, IL-12, IL-15 and IL-18 interaction with NK cells is not surpris- CD4+CD25+Foxp3+and able to secrete
and contact between NK cells and in- ing. During L. monocytogenesinfection, antiinflammatory cytokines (for exam-
fected macrophages (155). Liver granulocytes produce IL-12 and favor ple, IL-10 and TGF-β1) and thus behav-
macrophages (Kupffer cells) were also IFN-γproduction by NK cells (164). Dur- ing as suppressor cells. Alteration of the
shown to crosstalk with NK cells during ing L. pneumophilainfection, neutrophils immune system after sepsis is in part
activation in the presence of TLR2, TLR3 immediately produce IL-18, which is in- consecutive to the action of Tregs (175).
or TLR4 agonists, eitherin vitro or in dispensable for NK cell activation (165). Tregs and their cytokines behave as in-
vivo(156,157). The activation was shown As mentioned above for macrophages, hibitors of NK cell function (cytotoxicity
to depend on IL-18 and cell-to-cell con- NK cells can also activate neutrophils and IFN-γproduction) (176,177). Of
tact. Similar to the reciprocal activation and promote their survival; upregulate course, cells other than Tregs can down-
identified between DCs and NK cells cell surface expression of CD64, CD11b regulate NK cell function through the
(158), the crosstalk between and CD69; and enhance the production production of IL-10, despite its contra-
macrophages and NK cells is bidirec- of superoxide anions and heparin- dictory properties on NK cells (see
tional. For example, NK cells promote b inding epidermal growth factor (166). above); this is particularly the case of
phagocytosis of Escherichia coliby the This property observed when NK cells macrophages (148) and B-lymphocytes
macrophages through a CD40/CD154 were exposed to IL-15 and IL-18 partially (178). Myeloid-derived suppressor cells
interaction (154). NK cell activation depended on their production of GM- can impair NK cell development and
leads to a dramatic reduction in the CSF. The detailed nature of the bidirec- function (179) as well as Kupffer cells
number of intramacrophagic live Salmo- tional crosstalk between neutrophils and (156) and alveolar macrophages (135)
nella(155). In a CLP model of peritonitis, NK cells is now provided in an extensive via the release of IL-10, TGF-βor
macrophage phagocytosis, NO produc- review (167). prostaglandin E .
2
tion and IL-6 levels were decreased in Similarly, mast cells are key actors of Most interestingly, nonimmune cells
NK cell–depleted mice compared with innate immunity, thanks to their capacity can release NK-activating cytokines. This
controls (159). Indeed, coculture of NK to release preformed cytokines, particu- is the case of epithelial cells, which on in-
cells and macrophages significantly in- larly TNF-α(168). It was reported that, fection with Chlamydia trachomatiscan re-
creased activation levels of both cell in the presence of agonists for TLR3, lease IL-18, thus favoring the production
types, an activation determined to be TLR4 and TLR9, mast cells in coculture of IFN-γby NK cells (180). In addition,
cell-to-cell contact–dependent (154). Of experiments stimulated NK cells to pro- epithelial cells upon infection can in-
note is that the activation of monocyte duce IFN-γin a contact-dependent and crease their expression of NKG2D ligand,
and macrophages by TLR agonists leads TNF-α–independent manner (169). thus favoring a crosstalk with NK cells
to the expression of MHC class I–related Lymphocytes also interact with NK (162).
chain A (MICA), a ligand for NK group cells. B-lymphocytes were recognized
2 (NKG2) of receptors, member D long ago as accessory cells for the pro- BENEFITS VERSUS DISADVANTAGES OF
(NKG2D) and the ligand for the NKG2D duction of IFN-γby NK cells (170). In NK CELL ACTIVATION DURING
receptor, constitutively expressed on all return, IFN-γinhibits polyclonal B-cell BACTERIAL INFECTION
NK cells (160,161). The NKG2D receptor proliferation but favors the IgG2a re- As previously mentioned, NK cells are
is expressed predominantly on NK cells, sponse (171). Recently, it was reported closely associated with both the fight
NK T cells and T cells. This receptor rec- during a L. monocytogenesinfection that against bacterial infection and the dam-
ognizes infected cells through surface a subpopulation of B-lymphocytes ages associated with an overzealous in-
ligand expression on stressed cells. The (PDCA-1+Siglec-H–CD19+) activated flammatory response. According to ex-
proposed role of the NKG2D receptor in NK cells via secretion of IFN-α(172). perimental models, a beneficial or a
innate immune responses to cellular and Tlymphocytes also dialogue with NK deleterious contribution has been attrib-
tissue stress is based on the ability of the cells in a reciprocal fashion. For exam- uted to NK cells (Table 3). For example,
receptor to stimulate cytotoxic effects of ple, NK cells derived from pleural fluids when L. monocytogenes infection was in-
NK and Tcells and the production of of patients with tuberculosis pleurisy in- vestigated, Dunn and North (181) showed
IFN-γand TNF-α. In P. aeruginosa lung duce T-lymphocyte activation through that the early production of IFN-γby NK
infection, NKG2D is also involved in ep- ICAM-1 engagement (173). After lethal cells was essential for resistance to liste-
ithelial cell sloughing (162), whereas on injection of LPS, IL-18 was shown as riosis. In contrast, Teixeira and Kauf-
the other hand, IFN-γproduction by NK fundamental to trigger γδT cells to pro- mann (80) reported that NK cell deple-
278 | SOUZA-FONSECA-GUIMARAES ET AL. | MOL MED 18:270-285, 2012
REVIEW ARTICLE
Table 3.Examples of the half-angel half-devil role of NK cells during bacterial infections.
Role of NK cells and
experimental model Proof for NK cell role Reference
Beneficial
M. avium NK cell lysis of infected monocytes, Katz etal.J. Clin. Immunol.1990, 10, 71a;
NK cell lysis of infected macrophages, Bermudez etal.J. Leuk. Biol.1990, 47, 135;
Anti-NK1.1 depletion Harshan etal.Infect. Immun.1991, 59, 2818
Mycobacterium lepraemurium NK cell lysis of infected macrophages Denis Int. J. Immunopharmacol.1991, 13, 881
Mycobacterium tuberculosis Lysis of infected MØ by NK cells, Vankayalapati etal.J. Immunol.2005, 175, 4611;
Rag KO mice Feng etal.J. Immunol.2006, 177, 7086
Mycobacterium bovis IL-15 transgenic mice, Umemura etal.J. Immunol.2001, 167, 946;
reduced intracellular bacterial growth Denis etal.Tuberculosis.2007, 87, 53
L. monocytogenes Anti–NK cell depletion Dunn and North Infect. Immun.1991, 59, 2892
S. typhimurium Anti–asialo GM-1 depletion Schafer etal.Infect. Immun.1992, 60, 791
Salmonella choleraesuis Anti–IL-15 administration Hirose etal.J. Leuk. Biol.1999, 66, 382
Salmonella enterica Anti-NK1.1 depletion Ashkar etal.Infect. Immun.2009, 77, 214
Chlamydia trachomatis Anti–asialo GM-1 depletion, Tseng etal.Infect. Immun.1998, 66, 5867;
lysis of infected epithelial cells Hook etal.Clin. Exp. Immunol.2004, 138, 54
Chlamydia muridarum Anti–asialo GM-1 depletion Jiao etal.J. Immunol.2011, 187, 401
Staphylococcus aureus Anti-NK1.1 depletion, Nilsson etal.Clin. Exp. Immunol.1999, 117, 63;
IL-15 KO mice Small etal.J. Immunol.2008, 180, 5558
Polymicrobial peritonitis Anti–asialo GM-1 depletion Godshall etal.Shock.2003, 19, 144
Bordetella pertussis Anti–asialo GM-1 depletion Byrne etal.Eur. J. Immunol.2004, 34, 2579
Chlamydophila abortus Anti–asialo GM-1 depletion Buendia etal. J. Comp. Path.2004, 130, 48
Shigella flexneri Rag KO mice Le-Barillec etal.J. Immunol.2005, 175, 1735
Legionella pneumophila Anti–asialo GM-1 depletion Spörri etal.J. Immunol.2006, 176, 6162
Haemophilus influenza IL-15 KO mice Miyazaki etal.J. Immunol.2007, 179, 5407
Pseudomonas aeruginosa NKG2D activation and bacterial clearance Wesselkamper et al. J. Immunol. 2008, 1891, 5481
Francisella tularensis Anti–asialo GM1 depletion (granuloma formation) Bokhari etal.Infect. Immun.2008, 76, 1379
Deleterious
Pseudomonas aeruginosa Anti-NK1.1 depletion, Newton etal.Nat. Immun.1992, 11, 335;
role of NKG2D in epithelial cell injury Borchers etal.Infect. Immun.2006, 74, 2578
L. monocytogenes Anti-NK1 + depletion Teixeira and Kaufmann J. Immunol.1994, 152, 1873
LPS-induced Shwarzman reaction Anti-NK1.1 or anti–asialo GM-1 Heremans etal.Eur. J. Immunol.1994, 24, 1155
LPS-induced lethal shock NK1 + cells depletion Emoto etal.J. Immunol.2002, 169, 1426
E. coli Anti–asialo GM-1 depletion Badgwell etal.Surgery.2002, 132, 205
Polymicrobial peritonitis β2M KO + anti–asialo GM-1, Sherwood etal.Lab. Invest.2004, 84, 1655;
anti-NK1.1 or anti–asialo GM-1 Etogo etal.J. Immunol.2008, 180, 6334
Severe sepsis Enhanced levels of Granzyme Zeerleder etal.Clin. Immunol.2005, 116, 158
Streptococcus pyogenes Anti–asialo GM-1 depletion Goldmann etal.J. Infect. Dis.2005, 191, 1280
Streptococcus pneumoniae Scid mice + anti–asialo GM-1 Kerr etal.Microbes Infect.2005, 7, 845
H. pylori Increased infiltration of NK cells Kuo etal. World J. Gastroenterol.2005, 11, 4357
Mycobacteriainduced-colitis IL-10 KO mice Singh etal.BMC Immunol.2008, 9, 25
Ehrlichia chaffeensis NK cell depletion Stevenson etal.Am. J. Pathol.2010, 177, 766
aThe second number in each reference citation indicates the volume; the last number indicates the beginning page number.
tion led to an enhanced listerial clearing. notypic differences in NK cells were il- GM1 antibodies did not significantly
The fact that the route of infection (sub- lustrated in C3H/HeN and BALB/c mice modify the survival curves. In contrast,
cutaneous and intravenous, respectively) with P. aeruginosachronic lung infection NK cells contribute to the overzealous
and the mouse strains were different (182). production of inflammatory cytokines as-
may explain such a discrepancy. Indeed, In the CLP model of peritonitis, NK sociated with mortality of septic shock
it was proposed that CD8+T lympho- cells were shown to contribute to the (86,184). Most interestingly, in the latter
cytes may play a more important role early local and systemic control of the study, the beneficial effect of the deletion
than NK cells after intravenous L. mono- bacterial burden (183). In this study, how- of NK cells by either anti–asialo GM1 or
cytogenesinfection (81). In addition, phe- ever, depletion of NK cells by anti–asialo anti-NK1.1 antibodies was only seen
MOL MED 18:270-285, 2012 | SOUZA-FONSECA-GUIMARAES ET AL. | 279