Frontiers in Nephrology: The Varied Faces of Natural Killer Cells in Transplantation—Contributions to Both Allograft Immunity and Tolerance
Joshua N. Beilke* and
Ronald G. Gill
* Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, California; and Barbara Davis Center, University of Colorado Health Sciences Center, Denver, Colorado
Correspondence: Dr. Ronald G. Gill, Alberta Diabetes Institute, University of Alberta, Surgical-Medical Research Institute, 1074 Dentistry/Pharmacy Centre, Edmonton, Alberta, Canada T6G 2NB. Phone: 780-492-3077; Fax: 780-492-1627; E-mail: ron.gill{at}ualberta.ca
Natural killer (NK) cells are recognized for providing an importantearly innate immune response to viral and bacterial pathogensand for the surveillance of stressed and transformed autologouscells. However, with the exception of a pronounced role in allogeneichematopoietic stem cell rejection, it has been challenging toascribe the precise roles for NK cells in reactivity to tissueand solid-organ transplants. In general, NK cells initiate arapid, proinflammatory environment that is conducive to manyforms of effective immune host defense. This reactivity is oftenconsidered deleterious to allograft survival because NK cellsare implicated in promoting both acute and chronic graft injury.However, more recent findings indicate that NK cells can alsoplay a surprisingly profound role in allograft tolerance induction.This duality of function requires a reconsideration of the natureand consequence of NK cell reactivity during the allograft response.This review focuses on the differing "faces" of NK cells, especiallythe unexpected role of NK cells in allograft tolerance induction.
NK CELL RECOGNITION: BEYOND THE "MISSING SELF" CONCEPT
Unlike the rearranged antigen-specific receptor genes that areused by the adaptive immune system, natural killer (NK) cellsuse a variety of germline-encoded gene products for their recognitionarmament and so are categorized as part of the innate immunesystem. For quite some time, the primary paradigm describingNK cell killing was the notion of "missing self,"1 especiallyregarding deficient autologous MHC class I expression. Thatis, it is clear that the absence or reduction of MHC class Iexpression permits NK cell activation by transformed or infectedcells. However, during the past few years, it has become clearthat NK cell recognition involves a broad spectrum of both inhibitoryand activating receptor:ligand interactions. Both the activationand inhibition of NK cells predominantly involve interactionswith a series of MHC class I and class I–like molecules.2Thus, whereas classical MHC class I expression provides themajor source of inhibitory signals to NK cells, another seriesof more unusual, inducible class I–like molecules serveas signals of cellular stress, transformation, and infection.
Many NK receptors are encoded within the NK complex found onmouse chromosome 6 and human chromosome 12p13.2. Several excellentreviews have focused on these receptors and ligands2–6and so are not discussed in great detail. However, there arekey concepts regarding NK receptors that should be highlighted.It is important to note that NK cell reactivity is an integratedresponse controlled by both activating and inhibitory signals(examples of such receptor:ligands are summarized in Table 1).NK cell inhibition is achieved by a series of receptors, suchas much of the Ly49 family in mice (although some Ly49 receptorsare activating) and the killer cell Ig-like receptors foundon human NK cells.6 The reduction in self MHC class expressionby transformed or infected autologous cells or by MHC-disparateallogeneic cells accounts in part for the "missing self" responseby releasing such inhibitory stimuli. However, studies in thepast several years have identified another series inducibleMHC class I–like stimulating ligands that interact withNK activating ligands, such as NKG2D.7 Taken together, the absenceof self is not sufficient to promote NK cell killing but alsorequires the expression of appropriate activating ligands onthe target cell. It will be an ongoing challenge to dissectthe contribution of particular activating and inhibitory NKcell receptors to allograft immunity and tolerance.
Table 1. Examples of inhibitory and activating receptors on human and mouse NK cellsa
Because NK reactivity is affected by both positive and negativesignals, NK cells can kill self targets despite the presenceof inhibitory MHC class I molecules. For example, the "inducedself" retinoic acid early inducible-1 (RAE-1) ligand can triggerthe corresponding NK activating NKG2D receptor, resulting intumor cell killing.7 Importantly, enforced RAE-1 expressionin tumor cells can override inhibitory MHC class I signals andallow NK cell–mediated tumor rejection in vivo.8 Thismeans that NK cells can regulate autologous cells despite theexpression of inhibitory self MHC class I ligands, such as foundin NK killing of immature dendritic cells (DC)9,10 or "stressed"autologous T cells.11 This concept will be an important considerationregarding the potential role for NK cells in allograft toleranceinduction discussed next.
OVERLAP BETWEEN NK CELLS AND OTHER FORMS OF MHC CLASS I–DEPENDENT IMMUNITY
It is important to emphasize that some of the ambiguity in definingthe role of NK cells in allograft immunity and tolerance isdue to the overlap of function between NK cells and other typesof MHC class I–dependent cells and/or the considerablecross-talk between NK cells and other cells. For example, activatedCD8 T cells can express several NK cell–like receptorsthat can contribute to their effector function. Once activated,human CD8 T cells are capable of tumor cell killing throughthe NKG2D activating ligand (usually attributed to NK cells)independent of antigen-specific T cell receptor recognition.12Also, asialo GM1 is a cell surface marker that often is usedto identify and/or target NK cells but is also expressed onan important population of CD8 T cells.13,14 These potentialNK-like properties of CD8 T cells somewhat blur the traditionaldistinction between innate and adaptive immunity. Also, anotherimportant subset of nonclassical MHC class I–restrictedcells, the natural killer T (NKT) cell, shares properties withNK cells. Like NK cells, NKT cells express some NK cell–likereceptors, respond rapidly to appropriate stimuli, stimulateDC, and can contribute to antitumor immunity (reviewed by Kronenberg15).There are also interactions between NK and NKT cells duringthe initial innate response to tissue injury or pathogen exposure.However, unlike NK cells, NKT cells express CD3 and a relativelyrestricted, or "invariant," T cell receptor repertoire restrictedto nonclassical CD1 class I molecules presenting glycolipidmoieties. Thus, it is not surprising that it is challengingto distinguish NK cell–specific functions from those ofother MHC class I–dependent immune pathways.
CONTRIBUTIONS OF NK CELLS TO ACUTE AND CHRONIC ALLOGRAFT INJURY
Although our own interest has focused on the role of NK cellsin tolerance induction, it is important to note the multiplecontributions of these cells to both acute and chronic graftrejection. NK cells are widely known as mediators of MHC-disparatehematopoietic stem cell rejection16,17 and can constitute animportant barrier to T cell–directed tolerance protocolsfor achieving mixed hematopoietic chimerism.18 With this notableexception of bone marrow allografts, NK cells are not usuallyeither necessary or sufficient to mediate allograft rejectionindependent of an intact adaptive immune system. This is graphicallyillustrated by the findings that tissue and organ allograftsare accepted indefinitely in SCID and rag-1–/– micethat are NK replete but T and B lymphocyte deficient. This seeminglyancillary role for NK cells in transplant immunity makes definingtheir role in rejection difficult. However, there are a numberof ways in which NK cells promote the adaptive immune responseresulting in both acute and chronic allograft injury (illustratedin Figure 1).
Figure 1. Varied routes of natural killer (NK) cell involvement in acute and chronic allograft rejection.
NK cells have varied means of enhancing adaptive immunity19and probably can contribute to acute allograft rejection.20First, NK cells play an important role in "licensing" antigen-presentingcells, especially DC, resulting in DC maturation and subsequentT cell activation.21 Also, NK cells provide an early sourceof IFN- that helps tailor the generation of Th-1–likeimmunity by CD4 T cells.22,23 NK cells also can augment CD4T cell reactivity by a direct NK:CD4 T cell interaction.24 Allof these activities contribute to potentially graft-destructiveacute T cell reactivity. Although NK cells are rarely demonstratedto be necessary for the rejection of solid-organ allografts,there are exceptions. It is interesting that NK cells are requiredto trigger rejection of cardiac allografts in CD28–/–recipients, and this response requires the absence of self MHCexpression by the graft,25,26 a classic example of NK reactivityby the missing-self concept.
NK cells have also been implicated in promoting chronic allograftinjury. NK cells even infiltrate syngeneic kidney transplantsafter ischemic reperfusion injury and may contribute to chronicgraft pathology.27 Other studies suggest that NK cells can contributeto chronic allograft vasculopathy, possibly as a result of themissing-self MHC class I expression by allogeneic vascular endotheliumon the transplant.28,29 Such NK-dependent injury is IFN- dependent,29a finding that correlates with the requirement of conventionalCD4 T cells to mediate acute cardiac allograft rejection byand IFN-–dependent mechanism.30 Although it is not yetclear what molecular signals predominate the triggering of NKreactivity to allografts, this response is generally assumedto be harmful to graft survival.
AN UNEXPECTED CONTRIBUTION OF NK CELLS TO ALLOGRAFT TOLERANCE
Despite the ongoing correlation between NK cell reactivity andallograft rejection, it has become apparent that NK cells haveimportant regulatory properties31 that can actually facilitateallograft tolerance induction.32,33 We stumbled onto this unexpectedproperty of NK cells by studying the nature of tolerance topancreatic islet allografts after host treatment targeting eitherCD154 or CD11a (LFA-1).32 Because CD8 T cells have been shownto constitute a barrier to allograft tolerance induction afterco-stimulation blockade,14,34 we set out to study the propensityfor tolerance induction in MHC class I–deficient, -2 microglobulin(2m) knockout mice. Such animals are deficient in generalizedMHC class I–dependent immunity, including CD8 T cells.35To our surprise, tolerance induction absolutely required anintact host MHC class I pathway in that 2m-deficient hosts werecompletely resistant to induced allograft tolerance.32 BecauseNKT cells restricted to nonclassical MHC class I CD1 moleculeshave been implicated in allograft tolerance induction,36–38it was possible that this alternate 2m-dependent pathway wasrequired for tolerance. However, NKT cell–deficient CD1-knockoutmice were completely amenable to allograft tolerance induction,32a finding consistent with another similar study.33 NK1.1+ cellsthat were present in CD1-knockout mice were found to be requiredfor allograft tolerance, leading to the conclusion that NK cells,not NKT cells, were required for at least some forms of allografttolerance induction.32,33
WHAT ARE THE CELLULAR TARGETS OF NK CELL–MEDIATED IMMUNE REGULATION?
An ongoing question will center on identifying the cellulartargets of NK cells that result in tolerance induction. Bothantigen-presenting cells (APC) and T cells themselves are potentialobjects of NK cell regulation. There is clear precedence forDC being regulated by NK cells. Although NK cells can certainlydrive DC maturation, there is an important alternative outcomeof this NK interaction, resulting in the killing of the immatureDC.9,10 It is not yet clear which factors are critical for directinga positive versus negative impact of NK cells on immature DC.One straightforward pathway of NK cell regulation of alloimmunitycan be found in the direct elimination of donor-derived DC asa result of the missing-self property of MHC-disparate allografts.Yu et al.33 found that host NK cells rapidly destroyed MHC-disparateallogeneic DC but that semiallogeneic DC (i.e., host x donorF1 cells) were protected from such regulation (Figure 2). Theresult of rapidly eliminating donor DC would be the bluntingof the "direct" (donor APC-dependent) response33 that accountsfor the high frequency of alloreactive cells found in the nativeT cell repertoire. Thus, NK cells may essentially prune themagnitude of this direct antidonor reactivity by simply eliminatingthe primary donor-derived DC that are involved in activatingthe response. Alternatively, the extent of NK regulation ofrecipient DC that are involved in "indirect" (host APC-dependent)allograft antigen presentation is an important issue that iscurrently undefined.
Figure 2. Targeting of donor-derived dendritic cells (DC) by host NK cell as a result of "missing self."
Although such allogeneic DC elimination by NK cells can occur,this activity alone probably does not account for the entirerole for NK cells in allograft tolerance. If the sole propertyof NK cells is to eliminate donor DC via a missing-self response,then semiallogeneic allografts bearing self class I moleculesshould be protected from such donor DC elimination33 and sorender the host resistant to tolerance induction. However, wefind that recipients can be readily tolerized to (donor x host)F1allografts,32 suggesting that the role for NK cells in toleranceis more complex. An alternate view is that activated T cellsthemselves may serve as proximal targets of NK cell–mediatedregulation (Figure 3). For example, the NK activating ligandMHC class I–related chain A can be induced on stimulatedhuman T cells, serving as a potential target of the correspondingactivating NKG2D receptor. Importantly, such cellular "stress"signals on mouse T cells can make them vulnerable to NK killingdespite autologous MHC class I expression.11 This illustratesthe issue raised that NK cells actually integrate both stimulatingand inhibitory signals to determine the outcome of the NK response.It is intriguing that this NK killing of autologous stressedT cells was found to be perforin dependent,11 consistent withour own findings that tolerance induction to islet allograftswas both perforin and NK cell dependent in vivo.32 Thus, inthe presence of a tolerizing regimen, it is conceivable thatthe partial or inappropriate activation of host alloreactiveT cells results in the upregulation of their NK activating ligands,thereby increasing their vulnerability to NK cell–mediatedkilling. Further studies clearly will be necessary to test thisproposition.
Figure 3. Targeting of "stressed" autologous T cells by NK cells during tolerance induction.
We believe that DC and T cells are major candidate targets ofNK cell–mediated immune regulation. Of course, these arenot mutually exclusive pathways; NK cells may indeed directlyregulate both DC and T cells during tolerance induction. Itremains to be determined whether other types of myeloid lineagecells or lymphocytes (e.g., B cells) may also be involved inNK cell regulatory activity. Clearly, it will be important toclarify the pathways required for beneficial NK cell reactivityin allograft tolerance induction. Also, it is not known exactlywhich type of NK cell may be involved in promoting allografttolerance. For example, there has been a newly described "bitypic"NK-like DC (NK/DC) implicated in the regulation of autoimmunity.39Such cells can function in a veto-like capacity by regulatingT cells that interact with this cell. It is difficult to imaginehow such NK/DC can directly regulate donor-type DC as describedabove, but the potential role of this unusual cell type in regulatingallograft immunity must be considered in future studies.
WHAT IS THE RELATIONSHIP BETWEEN NK CELL AND REGULATORY T CELL REACTIVITY IN ALLOGRAFT TOLERANCE?
There has been a tremendous resurgence in the interest in regulatoryT cells (Treg) in the maintenance of allograft tolerance (reviewedby Wood et al.,40 Waldmann et al.,41 and Walsh et al.42). Althoughthis discussion largely centers on MHC class I–dependentreactivity, it is important to emphasize that induced allografttolerance is generally dependent on CD4 T cells. An unansweredquestion is whether there is a direct connection between NKcell function and Treg activity in the promotion of allografttolerance. To date, most published evidence favors the contrarynotion that there is mutual antagonism between NK cells andTreg.43 For example, CD4+CD25+ Treg generally inhibit NK cellreactivity,43 and in transplantation, such Treg can attenuateNK cell–mediated bone marrow allograft rejection.44 Thus,although there has been a suggestion that NK cells can alterDC function and promote Treg induction,45 there is little evidencethat NK cells generally promote Treg or vice versa. Rather,we propose that NK and Treg reactivities are temporally distinctprocesses during allograft tolerance induction. We found thatNK cells were required for tolerance induction only during theperitransplantation period. Within 3 wk after transplantation,NK cells were no longer required for long-term allograft survival.32However, there seems to be a requirement for Treg in the ongoingmaintenance of allograft tolerance. The connection between earlyinnate NK reactivity and longer term Treg activity in toleranceremains unclear. A conservative view is that there is no actualdirect interaction between NK cells and Treg in the developmentof tolerance induction. NK cells may be required early duringtolerance induction to restrain DC and/or T cells that can initiateallograft injury, whereas sustained allograft protection isachieved by a subsequent maturation of a regulatory T cell responsethat is enhanced by the tolerogenic regimen (Figure 4). Thus,it is possible the NK cells do not actually induce tolerance,per se, but simply permit allograft survival while a regulatoryresponse develops.
The regulatory potential of NK cells is only one facet of agrowing body of evidence indicating that several immune pathwaysthat are regarded as graft destructive can also participatein tolerance induction. Generally, the presence of proinflammatoryimmunity and cytolytic activity clearly correlates with allograftinjury. However, it is becoming increasingly apparent that thereis also a major regulatory role for many of these same effectorcells and molecules, including IFN-, perforin, and NK cells.Regarding IFN-, there are clear examples where this cytokinecan be essential for either CD430 or CD846 T cell–mediatedacute rejection and also for chronic rejection.29 However, thereis clearly another side to IFN- that can promote allograft survivaland tolerance. IFN- can actually have an early protective effecton allograft injury.47 Also, several studies show a major rolefor IFN- in promoting allograft tolerance48–50 and mayeven play an important role in ongoing allograft tolerance activitymediated by Treg.50
The cytolytic mediator perforin also demonstrates a marked "duality"in promoting either allograft rejection or tolerance. Althoughgene expression for the cytolytic mediators perforin and granzymesclearly correlates with graft rejection,51–53 perforinis also necessary for tolerance induction.32,54 The exact rolefor perforin in tolerance is not yet clear, but cytolytic moleculessuch as perforin55 and granzymes56 have been implicated in thefunction of Treg. Although cytotoxic activity by Treg has beenclearly demonstrated, our own results suggest that this is notrequired for long-term allograft survival. We found that thetransfer of perforin-replete NK cells was sufficient to restorelong-term allograft survival to otherwise perforin-deficientmice,32 arguing against an obligate role for perforin expressionby conventional T cells for graft survival.
This last point may help to resolve the seeming paradox betweenboth destructive and protective properties of these effectormolecules on allograft survival. It is highly likely that these"proinflammatory" pathways are compartmentalized by cell typeand/or by anatomic location to promote graft injury or survival,respectively. For example, alloreactive effector T cells expressingIFN- and perforin may well mediate acute or chronic graft injury.However, Treg and NK cells may use these same pathways to mediatethe regulation of alloimmunity. It will be an ongoing challengeto sort out the opposing roles of these effector pathways inallograft immunity and tolerance and to translate this informationinto clinically relevant therapeutic strategies to promote allograftsurvival.
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2240 - 2241.
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that helps tailor the generation of Th-1–like immunity by CD4 T cells.22,23 NK cells also can augment CD4 T cell reactivity by a direct NK:CD4 T cell interaction.24 All of these activities contribute to potentially graft-destructive acute T cell reactivity. Although NK cells are rarely demonstrated to be necessary for the rejection of solid-organ allografts, there are exceptions. It is interesting that NK cells are required to trigger rejection of cardiac allografts in CD28–/– recipients, and this response requires the absence of self MHC expression by the graft,25,26 a classic example of NK reactivity by the missing-self concept. 
-2 microglobulin (
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Abstract
NK CELL RECOGNITION: BEYOND...
