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. 2010 Nov;131(3):301–309. doi: 10.1111/j.1365-2567.2010.03337.x

The tortoise and the hare: slowly evolving T-cell responses take hastily evolving KIR

Jeroen van Bergen 1, Frits Koning 1
PMCID: PMC2996550  PMID: 20722764

Abstract

The killer cell immunoglobulin-like receptor (KIR) locus comprises a variable and rapidly evolving set of genes encoding multiple inhibitory and activating receptors. The activating receptors recently evolved from the inhibitory receptors and both bind HLA class I and probably also class I-like structures induced by viral infection. Although generally considered natural killer (NK) cell receptors, KIR are also expressed by a large fraction of effector memory T cells, which slowly accumulate during human life. These effector memory cells are functionally similar to NK cells, as they are immediate effector cells that are cytotoxic and produce IFN-γ. However, different rules apply to NK and T cells with respect to KIR expression and function. For example, KIR tend to modulate signals driven by the T-cell receptor (TCR) rather than to act independently, and use different signal transduction pathways to modulate only a subset of effector functions. The most important difference may lie in the rules governing tolerance: while NK cells with activating KIR binding self-HLA are hyporesponsive, the same is unlikely to apply to T cells. We argue that the expression of activating KIR on virus-specific T cells carrying TCR that weakly cross-react with autoantigens can unleash the autoreactive potential of these cells. This may be the case in rheumatoid arthritis, where cytomegalovirus-specific KIR2DS2+ T cells might cause vasculitis. Thus, the rapid evolution of activating KIR may have allowed for efficient NK-cell control of viruses, but may also have increased the risk that slowly evolving T-cell responses to persistent pathogens derail into autoimmunity.

Keywords: CMV, MHC/HLA, natural Killer cell Receptors/KIR, rheumatology, T cells

KIR: a rapidly evolving gene family

To ensure self-tolerance, most natural killer (NK) cells express inhibitory receptors that bind HLA class I molecules, including HLA-A, -B, -C and -E, expressed on all nucleated cells. HLA-E displays limited polymorphism, and is bound by the relatively non-polymorphic CD94/NKG2A lectin-like receptor. HLA-A, -B and -C display extensive polymorphism, and are bound by a similarly polymorphic family of receptors termed killer cell immunoglobulin-like receptors (KIR). Each inhibitory KIR gene encodes a receptor that binds a selected set of HLA class HLA-A, -B or -C alleles. Upon ligand binding, the receptors transmit an inhibitory signal via the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic tail, which inhibits NK-cell activation (Fig. 1) and thereby prevents attack of autologous tissue. Virus-infected cells, however, often lose HLA class I expression and can therefore be eliminated by NK cells. Driven by the diversification of HLA genes, the KIR gene family has also evolved rapidly.1

Figure 1.

Figure 1

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Killer cell immunoglobulin-like receptor (KIR) function on T and natural killer (NK) cells. On T cells (left), activating (KIR-S, green) and inhibitory (KIR-L, red) KIR mainly modulate signals induced by T-cell receptor (TCR) engagement. On NK cells (right), activating KIR can directly trigger effector functions, while inhibitory KIR interfere with signals induced by activating receptors such as activating KIR.

The lectin-like and immunoglobulin-like inhibitory receptors also have family members that are activating. In NK cells, CD94/NKG2C and activating KIR associate with the transmembrane adapter molecule DAP12, which transmits an activating signal via immunoreceptor tyrosine-based activation motifs in its cytoplasmic tail. The activating KIR most likely evolved to bind virally encoded HLA class I like molecules, allowing NK cells to kill infected cells.2,3 Ironically, these viral products may have evolved to evade NK-cell immunity by binding inhibitory NK-cell receptors. Activating KIR recently evolved from inhibitory KIR (Fig. 2a) through as few as five to seven nucleotide changes, which introduced a charged residue into the transmembrane domain to bind DAP12 (which predates the KIR and Ly49 genes by 300 million years) and eliminated the ITIMs.4 As they derive from inhibitory KIR with specificity for HLA class I, at least some of the activating KIR (KIR2DS1, KIR2DS4) have retained the ability to bind HLA class I.5,6 However, while the old inhibitory receptor was evolutionarily selected based on its ability to bind HLA class I, the new activating receptor gene would be selected based on its affinity for the viral homologue and might therefore ultimately lose its ability to interact with class I. In line with this idea, no measurable affinity for HLA class I could be demonstrated for KIR2DS2.7–9

Figure 2.

Figure 2

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The hare and the tortoise: rapid evolution of killer cell immunoglobulin-like receptors (KIR) and slow evolution of T-cell immune responses to persistent pathogens. (a) Multiple inhibitory KIR (KIR-L) carrying immunoreceptor tyrosine-based inhibitory motifs (ITIMs, red) rapidly arose from an ancestral KIR gene by duplication, mutation and recombination. Less than 20 million years ago, after the divergence of hominoids from Old World monkeys, short-tailed activating KIR (KIR-S) were derived from inhibitory KIR by mutation, introducing a charged residue (green) into the transmembrane (black) domain to bind DAP12 (which predates the KIR and Ly49 genes by 300 million years) and eliminating the ITIMs. Recombination between inhibitory and activating KIR subsequently allowed the coupling of this activating signalling unit to the extracellular domains encoding pre-existing inhibitory genes. (b) Naive virus-specific T cells emerging from the thymus can acquire KIR upon clonal expansion induced by infection, and persistent viruses induce a slow accumulation of KIR+ T cells. The expression of inhibitory KIR (KIR-L, red) may limit anti-viral responses by binding virally encoded HLA class I homologues (or HLA class I, not shown), while activating KIR (KIR-S, green) can boost these responses. If a virus-specific T-cell receptor (TCR) on a T-cell clone cross-reacts weakly with a self-antigen, then expression of an activating KIR recognizing HLA class I could unleash the latent autoreactivity of this clone.

Depending on one's KIR genotype, up to 14 different KIR genes are at hand.10 From these, individual NK cells randomly select KIR (usually 3–5) for expression, leading to a diverse NK receptor repertoire in which different KIR genes are expressed by overlapping subsets of the total NK-cell pool.11 Depending on one's HLA genotype, few or many of these will bind self HLA class I. As a result of the near-randomness of this process, potentially autoreactive NK cells arise that lack inhibitory or express excess activating receptors for self HLA class I.12 The most straightforward way to induce self-tolerance would be to eliminate such NK cells, but this does not appear to be an efficient process.13,14 Rather, these NK cells are present but hyporesponsive,15,16 which might explain why they are self-tolerant. Overall, every NK cell needs to balance the combination of NK receptors that it expresses and the signalling efficiency of these receptors to maximize responsiveness to pathogenic threat while maintaining self-tolerance.

To sum up, the rapidly evolving KIR gene family encodes a diverse set of activating and inhibitory receptors. HLA class I encodes all currently known ligands for the KIR but it is likely that persistent viruses encode HLA class I-like molecules that also bind both types of receptors. The KIR locus is extremely polymorphic and segregates independently of the similarly polymorphic HLA locus. Despite this, and despite the fact that individual NK cells express a virtually random selection of inhibitory as well as activating KIR, NK-cell tolerance is maintained.

KIR expression and function differ between NK and T cells

As more and more NK-cell receptor-specific monoclonal antibodies were developed, it turned out that these also stained T cells.17–22 What's more, the majority of human peripheral blood lymphocytes that express ‘NK-cell receptors’ are in fact T cells. The KIR are no exception: a sizeable fraction of memory T cells, effector memory T cells in particular,23,24 expresses KIR. The KIR are most likely acquired after the termination of T-cell receptor (TCR) rearrangements, as T-cell clones carrying identical TCR rearrangements can express highly diverse KIR patterns.25–27 In line with this, the proportion of KIR+ T cells – like effector memory T cells – keeps increasing with age.24,28 Along with the expression of KIR, these cells have often acquired additional receptors and functions normally associated with NK cells, such as the ability to lyse classical NK-cell targets like K562,20 almost as if these T cells harboured an innate wish to become NK cells. Hence, KIR expression may be a characteristic of T-cell responses that evolve slowly during one's lifetime, taking up more and more immunological space (Fig. 2b).

Even though there are phenotypic and functional similarities between NK cells and KIR-expressing T cells, the expression regulation, selection and function of KIRs are divergent (Table 1). The expression regulation of KIR differs both at the level of epigenetic modifications and transcription factors. In NK cells, methylation of CpG islands in the proximal KIR promoters appears to be an all-or-none phenomenon: CpG sites within the core promoters are either mostly methylated or mostly demethylated, and KIR genes with demethylated promoters are transcribed.29–31 The situation in T cells is more gradual: demethylation of KIR promoters is often patchy and increases as memory T-cell differentiation progresses.32 The size of the core promoter also differs: an approximately 120-base-pair sequence directly upstream of the translation initiation site can act as a minimal promoter in NK cells,33,34 but T cells require only the first approximately 60 bases upstream.34In vitro, this minimal T-cell promoter binds a different set of nuclear factors from NK and T cells.34 In line with this finding, the relative strengths of several KIR promoters differ greatly between NK- and T-cell lines, the strongest – KIR2DL4 – promoter in NK cells being the weakest in T cells.33,35 In agreement with these findings, NK-cell and T-cell KIR repertoires differ even within individuals,25,36 and the KIR2DL4 gene for example is transcribed by all NK-cell clones but not all T-cell clones.11,24,26,36 Furthermore, KIR2DL1 and KIR2DS1 are virtually absent from the CD4+ T-cell KIR repertoire, whereas KIR2DL2, KIR2DL3 and/or KIR2DS2 are over-represented among CD4+ CD28− T cells.24,36,37 Hence, KIR expression is regulated differently in T versus NK cells, and in line with this their KIR repertoires are also different (Table 1).

Table 1.

Differences between natural killer (NK) and T cells in killer cell immunoglobulin-like receptor (KIR) gene regulation, repertoire and function

NK T
Regulation Promoter methylation All-or-none29–31 Patchy32
Size minimal promoter 120–250 bp33,34 60 bp34
Transcription factors YY1, CRE/ATF, RUNX3, Sp134,35,85,86 YY1, CRE/ATF, RUNX3 (sites) not involved34
Repertoire KIR2DL1/S1 Roughly 15% of cells36 CD4+ CD28−: approximately 0%24,36,37
KIR2DL2/L3/S2 Roughly 30% of cells36 CD4+ CD28−: overrepresented24,36,37
KIR2DL4 100% of cells11 < 100%24,26,36
Tolerance ‘at least one’a No14,38 No24,25
‘licensing’b Yes15,39 Noc
Function Inhibitory KIR Inhibit (see Table 2) Inhibit (see Table 2)
Activating KIR Activate (see Table 2) Co-stimulate (see Table 2)
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a

Every cell expresses at least one inhibitory receptor binding self-HLA.11

b

The phenomenon that cells expressing at least one receptor for self-HLA are more responsive than cells that carry no such receptor.15,39

c

van Bergen, unpublished results.

The impact of one's HLA genotype on the combinations of receptors expressed by an individual's NK cells is small13 to non-existent.14 At any rate, NK cells lacking inhibitory receptors for self-HLA (uninhibited NK cells) are not, or are inefficiently, deleted,12,14,38 and this is also true for KIR-expressing T cells.24,25 Instead, uninhibited NK cells show reduced responsiveness to triggering of activating receptors.15,39 This potential tolerance mechanism is probably not operational in T cells, as KIR acquisition is a post-thymic event.25–27 In support of this idea, interferon-γ (IFN-γ) production in response to TCR/CD3 cross-linking does not differ between effector memory T cells that do or do not express self-specific inhibitory KIR (van Bergen, unpublished results). Therefore, the tolerance mechanisms proposed for NK cells (deletion, responsiveness modulation) do not appear to be operational in T cells (Table 1).

KIR-expressing T cells, like NK cells, are IFN-γ-producing cells capable of immediate cytolytic function.28 This holds true even for KIR+ CD4+ T cells,21,40 which possess cytolytic granules containing granzyme B. Similar to their function in NK cells, inhibitory KIR on CD8+ T cells generally inhibit cytotoxicity20,21,26,41–45 and IFN-γ production41,45,46 induced by TCR engagement (Fig. 1, Table 2). Their function in CD4+ T cells is less clear: although proliferation is consistently inhibited,27,40,47,48 an inhibitory effect on cytotoxicity and cytokine production is not always observed,21,27,40,46 indicating that the inhibitory KIR can uncouple T-cell effector functions. Thus, as in NK cells, inhibitory KIR generally inhibit T-cell effector functions, but in the case of CD4+ T cells this inhibition may hit only a selected set of effector functions (Table 2).

Table 2.

Modulation of T-cell functions by inhibitory (KIR-L) or activating (KIR-S) killer cell immunoglobulin-like receptors

CD4+ T cells CD8+ T cells
KIR-L KIR-S KIR-L KIR-S
Cytotoxicity Inhibit21a Trigger51b Inhibit20,21,26,41–45,71 Co-stimulate48
No effect40 No effect36 No effect20 No effect45
Proliferation Inhibit27,40,47,48 Co-stimulate36,47,48 Inhibit71
Cytokines Inhibit40,46 Co-stimulate48,53 Inhibit41,45,46,71 Co-stimulate48
No effect27 Trigger48,53 No effect45
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a

van Bergen, unpublished results.

b

In DAP12+ clones.

The mouse Ly49 locus encodes multiple inhibitory and activating receptors that serve the same functions as the KIR in humans. Intriguingly, mouse T cells express only inhibitory Ly49 molecules,49 whereas human T cells can also express activating KIR.47 Activating KIR can independently activate NK cells by transmitting a signal via the adapter molecule DAP12 (Fig. 1),50 and a minor fraction of KIR+ CD4+ and CD8+ T cells can also express DAP12, thereby bypassing the need for TCR-triggering for activation.25,51,52 In the majority of T cells, however, these KIR function as co-stimulatory receptors that boost the response to TCR cross-linking (Fig. 1).47 Consistent with this finding, the majority of CD4+ T cells do not use DAP12 for signal transduction, but an as yet unidentified adapter molecule.53 Uncoupling of effector functions has also been observed for activating KIR, as KIR2DS2 on CD4+ CD28− T cell clones was shown to co-stimulate proliferation but not cytotoxicity.36 So, while engagement of activating KIR directly activates NK-cell cytotoxicity and cytokine production, on T cells it can have highly divergent functional consequences (Fig. 1, Table 2).

To sum up, KIR expression and function follow a different set of rules in T cells compared with NK cells (Table 1). First, in T cells KIR use a smaller minimal promoter, which is gradually demethylated to bind a distinct set of transcription factors. Second, the T-cell and NK-cell KIR repertoires are different. Third, the tolerance mechanisms proposed to contain NK cells do not seem to apply to T cells. Finally, KIR tend to modulate signals driven by the TCR rather than to act independently (Fig. 1, Table 2), and may use different signal transduction pathways to modulate only a subset of effector functions. The fact that KIR are found at high frequencies on T cells with a late memory phenotype that gradually accumulate during human life suggests that they modulate slowly evolving T-cell responses to persistent pathogens (Fig. 2b).

KIR in CMV infection

Cytomegalovirus (CMV) has provided a favourite infection model for studying human and mouse NK and T cells. CMV is a continuously reactivating DNA virus with a large genome that encodes numerous proteins interfering with the host immune response. More than half the human population acquires this virus during childhood and carries it around for the rest of their lives, usually without noticing. CMV is not intrinsically harmless, however, as it can be life-threatening in immunocompromised individuals. It may also be associated with immune system dysfunction and lower life expectancy in people over the age of 80 years.54 Clearly, a functional immune system is critical for an asymptomatic course of the infection.

The immense impact of CMV on the evolution of the immune system is illustrated by the fact that the mouse genome encodes an activating NK receptor (Ly49H) specific for a viral MHC class I decoy molecule: murine CMV (MCMV) m157.2,3 Upon infection, there is a selective expansion of Ly49H+ NK cells,55 followed by a contraction phase and the persistence of memory NK cells.56 No activating KIR specific for CMV has been identified in humans, although KIR genotypes encoding multiple activating KIR genes (KIR B-haplotypes) are associated with protection from CMV infection after bone marrow and kidney transplantation.57,58 Furthermore, human CMV (HCMV) seropositive individuals carry greater numbers of CD94/NKG2C+ NK cells in their blood.59 It is therefore plausible that certain human activating NK receptors also bind human CMV-encoded HLA class I-like molecules or other surface structures induced by HCMV infection.

Not only does CMV infection leave a lasting imprint on the NK-cell repertoire, it also drastically changes the composition of the T-cell compartment. In CMV-seropositive humans, on average at least 10% of both the CD8+ and CD4+ memory T-cell compartments consist of CMV-specific cells.60 This frequency increases markedly with age61–63 and in nonagenarians T cells specific for a single epitope (HLA-A*0201/NLVPMVATV(pp65)) can constitute nearly 30% of all circulating CD8 T cells.62 Compared with other viruses, CMV-specific memory T cells are strongly biased towards an effector memory phenotype, characterized by the absence of CD27, CD28 and CCR7, and by the presence of CD57,64–66 and this bias becomes even more pronounced in old age.62 As a result, CMV carriers can be identified by the presence of CD4+ CD28− T cells in peripheral blood,65,66 while CD8+ CD28− T cells are also increased compared with CMV-negative individuals.67

As a large proportion of effector memory cells express KIR, it was expected that many CMV-specific memory T cells would express KIR. In line with this idea, CMV infection is associated with the accumulation of effector memory CD8+ T cells expressing KIR.68 However, only a small minority of CMV-specific CD8+ T cells identified using HLA/peptide tetramers [in most cases HLA-A*0201/NLVPMVATV(pp65)] stains with KIR antibodies.28,69–71 In fact, KIR expression was threefold less frequent on tetramer-positive cells than on the total CD8+ T-cell population.70 Also in the CD4+ T-cell compartment, KIR were detected on a small minority of CMV-specific cells, but in contrast with CD8+ cells, KIR expression was about fourfold more frequent on cells responding to CMV lysate compared with non-responding cells.27 The global picture emerging from these data is that a fraction of CMV-specific memory T cells expresses KIR, and that at least in the CD4 compartment KIR expression is associated with memory function.

Taken together, the immune response to CMV is a good example of a slowly evolving T-cell response to a persistent pathogen. The CMV engages in a relatively peaceful and long-lasting co-existence with its host. The host immune response is characterized by a gradual accumulation of effector memory T cells that can express KIR. The expression of inhibitory KIR might – together with other inhibitory receptors such as PD-1, LAG-3 and CTLA-4 – dampen long-lasting and expanding anti-viral responses that do more harm than good. The expression of activating KIR on CMV-specific T cells on the other hand would have the opposite effect. If one of the CMV-specific TCR cross-reacted weakly with a self-antigen, the T cell in question might even turn against its host (Fig. 2b).

KIR in rheumatoid arthritis and its complications

Given the role of KIR in regulating lymphocyte responses and the extremely polymorphic nature of the KIR, it had long been suspected that particular KIR constellations would be associated with disease susceptibility. Indeed, the past decade has witnessed a flurry of papers describing associations between the presence of one or more activating KIR and autoimmune diseases such as psoriasis,72,73 psoriatic arthritis,74,75 scleroderma76 and type I diabetes.77,78 Rheumatoid arthritis (RA) was the first disease in which such an association was found: the KIR2DS2 gene is associated with the presence of vasculitis in RA patients.79

In a case–control study, the activating KIR2DS2 was found to be present in 83% of RA patients with vasculitis, compared with < 50% of healthy donors and patients with uncomplicated RA.79 This finding was reproduced in an independent cohort by Majorczyk et al.,80 who noted that other extra articular manifestations of RA were also associated with the presence of KIR2DS2, albeit less strongly. Of note, KIR2DS2 is in linkage disequilibrium with other KIR genes, most notably KIR2DL2, which makes it difficult be certain that KIR2DS2 is the causative gene. While the ligand for KIR2DS2 remains to be identified, its homology with KIR2DL2, which binds a subset of HLA-C alleles characterized by an asparagine at position 80 of the α-chain (group 1 HLA-C), has been taken as evidence that it too would bind this set of HLA-C molecules. However, this idea remains unsubstantiated7–9 and no association between group 1 HLA-C alleles and vasculitis was found.79 Rather, HLA-Cw3 but not other HLA-C group 1 alleles were associated with vasculitis.79 In summary, the activating KIR2DS2 probably contributes to the development of vasculitis in patients with RA, but it is unclear which ligand triggers it.

One of the hallmarks of severe extra articular complications of RA such as vasculitis is the presence of a greater than 10-fold expanded effector memory CD4+ T-cell subset (compared with uncomplicated RA), defined by the absence of surface CD28.81 In three patients with RA vasculitis, the majority of cloned blood CD4+ CD28− T cells expressed KIR2DS2 transcripts, whereas such transcripts were hardly ever detected in CD4+ CD28− T cells from two healthy control donors, despite the presence of the KIR2DS2 gene in these controls.79 No other KIR gene showed such a consistent difference in expression between patient and control CD4+ CD28− T cells.79 KIR2DS2 may act as a selective co-stimulatory receptor on CD4+ CD28− T cells, boosting their proliferation and IFN-γ production, but not cytotoxicity.36,79 The expression and function of KIR2DS2 on CD4+ CD28− T cells may therefore explain its association with complications in RA.

In the healthy population, CD4+ CD28− T cells are detected only in CMV-seropositive individuals and respond to CMV. Similarly, in RA patients, CD4+ CD28− T cells were detected only in CMV-seropositive patients.27,65,82 In these patients CMV-specific T cells were far more frequent among CD4+ CD28− T cells relative to CD4+ CD28+ T cells.27,82,83 Furthermore, the proliferative response of CD4+ CD28− T cells to CMV was equal to the response to plate-bound anti-CD3.83 Finally, the TCR repertoires of CD4+ CD28− T cells expanded in vitro by stimulation with CMV or anti-CD3 were virtually identical.83 Taken together, it is likely that most, if not all, CD4+ CD28− T cells in RA patients are CMV-specific.

To confirm that CD4+ CD28− T cells in RA patients are CMV-specific, we randomly cloned large numbers of CD4+ CD28− KIR+ T-cell clones from two RA patients.27 In contrast with control CD4+ CD28+ KIR− clones, a large fraction of these clones proliferated specifically in response to a CMV-lysate.27 In line with the bias observed in CD4+ CD28− T cells in healthy donors and RA patients,24,36 the large majority of these CMV-specific CD4+ CD28− KIR+ T-cell clones expressed the inhibitory KIR2DL2, KIR2DL3 or the activating KIR2DS2 (unpublished results). Although our clones stem from RA patients without severe extra articular complications, these findings do suggest that the potentially pathogenic CD4+ CD28− KIR2DS2+ T cells in RA vasculitis patients are also elicited by CMV infection. It is possible that these cells lyse CMV-infected endothelial cells and thereby stimulate vascular inflammation,66 but this would require the presence of CMV in a relatively large proportion of endothelial cells. Alternatively, these cells may cross-react with autoantigens involved in RA, and costimulation via KIR2DS2 might allow overt autoreactivity.

Virus-specific T cells expressing activating KIR, culprits in autoimmunity?

Based on the currently available data, the following scenario emerges (Fig. 2). In the beginning, at least 100 million years ago, the rapidly evolving KIR gene family (the hare) encoded only inhibitory receptors specific for HLA class I (Fig. 2a), allowing NK cells to identify and attack diseased cells with perturbed HLA expression. T cells may have acquired the ability to express these receptors and used these to reduce the activities of expanding anti viral T-cell responses to limit collateral damage.

Later on, persistent viruses developed genes encoding decoy HLA class I molecules, allowing them to evade NK-cell responses by binding inhibitory KIR. As a swift counterinsurgency measure on an evolutionary time scale, < 20 million years ago, some of the genes encoding these inhibitory KIR morphed into activating receptor genes, helping NK cells combat infection (Fig. 2a). Any remaining reactivity with self HLA did not lead to autoreactive NK cells, as these would be neutralized by NK-cell tolerance mechanisms. However, as T cells had already acquired the ability to express inhibitory KIR, they had no choice but to also express these novel activating KIR (Fig. 2b).

Unfortunately, the expression and function of activating KIR in T cells is not as tightly controlled as in NK cells, and T cells expressing activating KIR reactive with self-HLA would not be restrained by stringent tolerance mechanisms, particularly because T cells acquire KIR well after thymic selection (Fig. 2b). Instead of limiting antiviral T-cell responses, activating KIR would be expected to boost these (Fig. 2b). To make matters worse, memory T cells specific for persistent viruses and expressing activating KIR accumulate in the course of a human lifetime (the tortoise). This increases the risk of uncontrolled T-cell responses leading to tissue damage if any of the virus-specific TCR have some degree of cross-reactivity with a self-antigen (Fig. 2b).

The case of rheumatoid vasculitis may fit this scenario. In RA vasculitis, a massive expansion of CD4+ CD28− CD4 T cells is observed, and these T cells are probably induced by and specific for CMV. Furthermore, in individuals carrying the activating KIR2DS2 gene many of these T cells express this activating KIR. The current challenge is to determine whether any of these CMV-specific TCR cross-react with autoantigens, and to identify ligands for KIR2DS2. Even in the absence of a known ligand, the therapeutic potential of antibodies blocking activating KIR such as KIR2DS2 may be explored to prevent exacerbation of autoimmune disease, inspired by current clinical trials using humanized antibodies blocking inhibitory KIR to fight cancer.84

Acknowledgments

The authors wish to express their gratitude to René Toes, Mariet Feltkamp and Tom Huizinga for their long-standing collaboration. For the work described in this review, JvB was supported by NWO VENI grant 916·36·025 and by the Macropa Foundation.

Disclosures

The authors have no financial disclosures.

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