The role of KIR and HLA interactions in pregnancy complications.

Combinations of KIR and HLA genes associate with pregnancy complications as well as with many other clinical scenarios. Understanding how certain KIR and HLA genes influence the biology of a disease is, however, a formidable challenge. These are the two most variable gene families in the human genome. Moreover, the biology of a disease is best understood by studying the cells of the affected tissue. Natural Killer (NK) cells express KIR and are the most abundant leukocytes in the uterus. Most of our knowledge of NK cells is based on what we have learned from cells isolated from blood, but these are different from their tissue resident counterparts, including uterine NK (uNK) cells. Reproductive immunology faces an additional challenge: Two genotypes must be considered because both maternal and foetal HLA class I molecules may influence the outcome of pregnancy, most likely through interactions with maternal KIR expressed on uNK cells. Maternal uNK cells are not spontaneously cytotoxic and instead engage in interactions with trophoblast. We hypothesise that these interactions regulate allocation of resources between the foetus and the mother and may go wrong in diseases of pregnancy.

Consistent beneficial effects of killer cell immunoglobulin-like receptor 2DL3 and group 1 human leukocyte antigen-C following exposure to hepatitis C virus.

UNLABELLED: Natural killer cells are a key component in the immune control of viral infections. Their functions are controlled by inhibitory receptors for major histocompatability complex (MHC) class I, including the killer cell immunoglobulin-like receptors (KIR). KIR2DL3 in combination with its cognate human leukocyte antigen (HLA)-C ligand has been shown to be associated with spontaneous resolution of viremia following hepatitis C virus (HCV) infection. In order to determine if this gene combination is advantageous across all potential outcomes following HCV exposure, we studied individuals with apparent resistance to HCV infection who remain seronegative and aviremic despite long-term injection drug use and also individuals chronically infected with HCV who successfully clear HCV with treatment. Homozygosity for KIR2DL3 in combination with group 1 HLA-C allotypes was more frequent in exposed seronegative aviremic individuals as compared to those with chronic HCV (25.0% versus 9.7%, P = 0.003, odds ratio [OR] = 3.1, 95% confidence interval [CI] = 1.3-7.1) in a model similar to that found for those spontaneously resolving HCV. In individuals undergoing treatment for HCV, those with KIR2DL3 and group 1 HLA-C were more likely to make a sustained virological response (SVR) (P = 0.013, OR = 2.3, 95% CI = 1.1-4.5). KIR and HLA-C protection in both treatment response and spontaneously resolving HCV was validated at the allelic level, in which KIR2DL3-HLA-Cw*03 was associated with SVR (P = 0.004, OR = 3.4, 95% CI = 1.5-8.7) and KIR2DL3/KIR2DL3-HLA-Cw*03 was associated with spontaneous resolution of HCV infection (P = 0.01, OR = 2.3, 95% CI = 1.2-4.4). CONCLUSION: KIR and HLA-C genes are consistently beneficial determinants in the outcome of HCV infection. This advantage extends to the allelic level for both gene families.

Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivo.

Natural killer (NK) cells are lymphocytes of the innate immune system able to recognize and kill tumors lacking self-MHC class I molecules. This "missing-self" recognition is mediated by the lack of engagement of MHC class I-specific inhibitory NK cell receptors that include the killer cell Ig-like receptors (KIR) in humans and Ly49 molecules in mice. A promising immunotherapeutic strategy against MHC class I(+) cancer cells is to block NK cell inhibitory receptors using monoclonal antibodies (mAb). However, interactions between MHC class I molecules and their inhibitory receptors are also required for the acquisition of NK cell functional competence, a process referred as to "education." In addition, inhibitory receptors are involved in self-tolerance on educated NK cells. Here, we developed a preclinical mouse model in which all NK cells are educated by a single transgenic inhibitory receptor, human KIR2DL3, through the engagement with its HLA-Cw3 ligand. This approach revealed that NK cells could be reprogrammed to control the development of mouse syngenic tumors in vivo. Moreover, in vivo anti-KIR mAb treatment induced the killing of HLA(+) target cells without breaking self-tolerance. Finally, the long-term infusion of anti-KIR mAb neither abolished NK cell education nor tumor cell recognition. Therefore, these results strongly support the use of inhibitory receptor blockade in cancer patients.

Cutting edge: selective expression of inhibitory or activating killer cell Ig-like receptors in circulating CD4+ T lymphocytes.

Apart from NK cells, TCRgammadelta and CD8+ T cells, killer cell Ig-like receptor (KIR) expression was described on a minor subset of CD4+ T cells. However, their functions remain to be elucidated in this latter lymphocyte population. We demonstrated that KIR2DL2/L3 (CD158b) and KIR2DS2 (CD158j) transcripts were synthesized by sorted CD4+CD158b/j+ T cells obtained from healthy individuals. In contrast, we observed that only the inhibitory or activating receptor was expressed at the cell surface according to the donor tested. In CD158b-expressing cells, KIR triggering leads to an inhibition of the CD3-induced cell proliferation and Erk activation, and the receptor exhibits an activation-dependent tyrosine phosphorylation and association with the Src homology 2-containing phosphatase 1. In CD158j-positive cells, KIR-engagement results in an enhanced CD3-mediated cell growth and Erk phosphorylation. Our results suggested that, in contrast to NK cells, the functions of KIR in CD4+ T lymphocytes might derive from a selective expression of their activating or inhibiting forms.