We show that KIR2DL2
enhanced several independent HLA class I-mediated effects in two unrelated viral infections. In HTLV-1 infection, KIR2DL2
enhanced the protective and detrimental effects of HLA-C*08
respectively on disease status. KIR2DL2
also enhanced the association between C*08
and low proviral load in ACs and between B*54
and high proviral load in HAM/TSP patients. Additionally, KIR2DL2
enhanced the protective effect of HBZ binding by multiple HLA molecules. Strikingly, on stratifying by KIR2DL2
, we observed, for the first time, a protective effect of C*08
on pvl in HAM/TSP patients and explained the lack of impact of B*54
on pvl in ACs. In HCV infection, KIR2DL2
enhanced the protective effect of B*57
on spontaneous clearance and the association between B*57
and low viral load in chronic carriers; for both clearance and viral load a progressive effect with KIR2DL2
copy number was observed. This progressive effect is consistent with reports of an association between KIR gene copy number and the frequency of cell-surface expression of the respective KIR molecule 
There are two mechanisms by which KIR2DL2 could act: it could enhance either NK-mediated or T cell-mediated immunity. That is, NK cell killing of virus-infected cells could be altered by KIR2DL2 expression or, alternatively, the virus-specific CD8+ T cell response could be modified by KIR2DL2 expression (on NK cells or T cells). Two observations indicate that it is the T cell response that is more likely to be enhanced. First, strong binding of HBZ viral peptides via multiple different HLA-A and B molecules was associated with asymptomatic status 
and this protective effect was enhanced by KIR2DL2
. KIR2DL2 is not known to bind HLA-A or–B molecules (with the exception of B*4601 and B*7301) 
so it is unlikely that the enhancement of the protective effect of binding HBZ by KIR2DL2 is due to direct binding between KIR2DL2 and HBZ peptide in the context of HLA-A and –B molecules. Furthermore, although NK cells exhibit peptide dependence 
, it is hard to reconcile protein-specificity via multiple HLA molecules with an NK cell-mediated mechanism. Second, the KIR2DL2
enhancement could not be explained by binding between KIR2DL2 and any of the 3 HLA class I molecules investigated. One further observation also suggests a T cell-mediated mechanism. Two protective genotypes in HCV infection that are postulated to operate via innate immune mechanisms 
(namely a SNP upstream of IL28B
had no impact on viral load in chronic infection 
. The authors hypothesised that this was because innate barriers offer little protection once overcome. In contrast, the KIR2DL2/B*57
effect that we report here had a significant impact on viral load: again, this is perhaps more consistent with adaptive immunity.
Our results indicate that KIR2DL2
enhances HLA class 1-restricted CD8+ T cell-mediated adaptive immunity. KIRs on both NK cells and CD8+ T cells have been reported to shape adaptive immunity 
. Of particular interest are reports 
that inhibitory KIRs on CD8+ T cells promote the survival of a subset of memory phenotype CD8+ αβ T cells with enhanced cytolytic potential (Tm1 
) by reducing activation-induced cell death. Ugolini et al suggested that this phenomenon helps maintain specific CD8+ T lymphocytes during chronic viral infection 
. Tm1 cells have been described in both HTLV-1 and HCV infections, where they constitute a minority of virus-specific CD8+ T cells but the majority of perforin-bright cells 
. Consistent with our findings, these studies showed that the HLA molecule that restricts the T cell whose survival is promoted was independent of the HLA-C molecules that ligated the KIR 
. We postulate that, in the face of chronic antigen stimulation, protective T cells survive longer if they carry KIR2DL2
and therefore exert stronger protection. Likewise, T cells restricted by HLA alleles associated with increased disease susceptibility also survive for longer in the presence of KIR2DL2
and so are more detrimental (). Hence, KIR2DL2
enhances both protective and detrimental HLA class I associations.
Postulated mechanism: KIR2DL2 reduces clonal exhaustion of CD8+ T cells and is necessary for an effective immune response in the face of chronic antigen stimulation.
Alternatively, it is known that NK cells kill activated T cells and that this killing is reduced by inhibitory KIR 
. So again, T cells restricted by protective and detrimental HLA class I molecules may survive longer in the presence of inhibitory KIR and thus the protective and detrimental associations would be enhanced.
Ugolini et al proposed that inhibitory KIRs promote T cell survival by increasing the activation threshold of T cells. This may explain why the HLA-A*02
protective effect in HTLV-1 is not significantly enhanced by KIR2DL2
. A*02 molecules bind peptides significantly more strongly than other alleles (section 9 in Text S1
) and the immunodominant HTLV-1 peptide Tax 11-19 is bound exceptionally strongly. Therefore, even if the T cell activation threshold were increased, the strength of signalling may remain above the threshold and consequently the A*02
protective effect cannot be enhanced.
Why does KIR2DL2 enhance T cell responses whereas the other inhibitory KIRs apparently do not? The effect of KIR2DL2 may be most apparent because KIR2DL2 is present at informative frequencies and its C1 and C2 ligands are ubiquitous; i.e. unlike the other KIR every individual carries a KIR2DL2 ligand.
It will be important to determine whether inhibitory KIRs play a similar role in enhancing CD8+ and possibly CD4+ T cell-mediated immunity to other pathogens and in autoimmune disease. KIR-expressing virus-specific CD8+ T cells have been reported in other chronic infections including HIV-1, CMV and EBV 
. Furthermore, in HIV-1 infection, high expression alleles of an inhibitory KIR, KIR3DL1
, in the context of HLA-Bw4I
have been associated with slow progression to AIDS 
. In order to explain protection by an inhibitory KIR the authors proposed a model based on NK cell development. Our results suggest an alternative explanation, i.e. that KIR3DL1
enhances protective HLA-B-restricted responses to HIV-1.
In contrast to previous studies of KIR genotype, which investigated the antiviral action of NK cells, we investigated the impact of KIRs on HLA class I-mediated antiviral immunity. We find a clear and consistent effect of KIR2DL2. The effect sizes are striking: KIR2DL2 homozygotes with B*57 are almost 5 times more likely to clear HCV infection spontaneously; if they fail to clear the virus they have a viral load that is reduced by 6.5 logs. Until now, the advantages offered by inhibitory KIRs in virus infections have been unclear. Our data support an alternative role in which inhibitory KIRs enhance both beneficial and detrimental T cell-mediated immunity in persistent viral infection.