Altered Natural Killer Cells in Type 1 Diabetic Patients

Abstract

Evidence from animal models suggests that natural killer (NK) cells can be important players in the development of type 1 diabetes, although data in humans are still sparse. We studied the frequency and activation state of blood NK cells at different stages of human type 1 diabetes, and whether genetic or phenotypic NK cell peculiarities could be associated with an early onset of diabetes. The onset period is marked by a slight reduction in blood NK cells, but these are unusually activated in some patients (␥-interferon expression). This activation status does not correlate, however, with a particularly young age at onset. In contrast, NK cells in patients with long-standing type 1 diabetes had a markedly lower expression of p30/p46 NKactivating receptor molecules compared with those of control subjects. A slightly decreased expression of NKG2D in all type 1 diabetic patients relative to control subjects was observed, independent of the duration of disease, parallel to prior observations in the NOD mouse. Finally, type 1 diabetic patients had an increased frequency of KIR gene haplotypes that include the activating KIR2DS3 gene, with a genetic interaction between the KIR and HLA complexes. The reduced activation of NK cells in individuals with long-standing type 1 diabetes would seem to be a consequence rather than a cause, but other peculiarities may relate to type 1 diabetes pathogenesis. Diabetes 56: 177-185, 2007

Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A*29-positive individuals

“…Supporting this model was the elution of retinal autoantigens from HLA-A29 molecules. 55 Predominance of KIR2DS2, 2DS3 and 2DS4, the genes implicated in autoimmune diseases [56][57][58] in BCR patients compared to HLA-A*29-matched controls, suggests that these aKIR receptors may enhance the T-cell autoreactivity. Although the direct role of NK cells in BCR pathogenesis is not clear, the genetic data presented herein indicate that KIR-HLA combinations likely influence both CTL and NK cell responses toward tolerance in controls and autoimmunity in BCR patients ( Figure 5).…”

“…Relatively weaker inhibitory signals triggered by the predominant interactions of KIR2DL2/3 þ HLA-C1 and KIR3DL1 þ HLA-Bw4 T80 in patients may be sufficient to establish NK cell tolerance to self in the resting state, 27 but may be easily overcome by activating signals triggered in response to stress such as infection, leading to disease. The preponderance of autoimmunity- iKIR+HLA only iKIR+HLA+aKIR *** associated activating receptors KIR2DS2, 2DS3 and 2DS4 [56][57][58] in patients suggests that the interaction between these aKIRs and determinants expressed on the surface of stressed intraocular tissue trigger signals that may overcome the weaker inhibition, favoring localized NK cell hyperresponsiveness against self. Of note, individuals carrying the compound genotype (KIR2DL2/3 þ HLA-C1, KIR3DL1 þ HLA-Bw4 T80 and KIR2DS2/S3/S4) are extremely rare in black and Asian populations, 47 which is consistent with the epidemiology of BCR.…”

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

“…The reasons for the lower cytotoxicity displayed by NOD NK cells are likely multifactorial, but previous studies of NK cells from human T1D patients show significantly lower cytotoxicity and decreased expression of activating receptors. 8,50 The observed cytotoxicity against CHO targets and the unusually large number of activating Ly49 in NOD mice, is especially intriguing in light of recent reported correlations between diabetes incidence and the number of activating KIR expressed by an individual's NK cells. 8,25 Supporting evidence for this hypothesis is found in the observation that disease incidence is reduced in NOD mice congenic for the B6 NKC, 11 which encompasses the B6 Ly49 region and contains only two functional activating Ly49 in contrast to the seven predicted for NOD.…”

“…An early study demonstrated that diabetic patients have lower NK activity compared to healthy controls, 7 whereas a second group found that NK cells isolated from diabetic patients showed an activated phenotype compared to NK cells from healthy controls. 8 Several recent studies have reported abnormal NOD NK cell functions and may be indicative of a possible association between diabetes development and NK cell dysfunction. [9][10][11] Cytotoxicity of NK cells from NOD mice against NK-sensitive tumor cell targets is lower than the killing activity from NK cells of nondiabetic mice.…”

“…These individuals generally have an increased number of activating KIR in their genome compared to healthy controls or are more likely to possess KIR haplotypes containing specific activating KIR. 8,25 Mapping studies in the NOD mouse model have shown that a diabetes susceptibility locus (idd 6) is present on chromosome 6 near the Ly49 gene cluster. 26 In agreement with this finding, NOD mice congenic for C57BL/6 (B6) NK1.1, a marker near the Ly49 cluster, manifested reduced disease incidence and improved NK and NKT cell performance as compared to wild-type NOD mice.…”