Background: Dysbiosis of the intestinal microbiota is implicated in Crohn's disease (CD) and may play an important role in triggering postoperative disease recurrence (POR). We hypothesized that the fecal microbial recolonization process after ileocecal resection differs between patients developing recurrence and patients remaining in remission, and further aimed to identify other factors influencing the microbial composition. Methods: Fecal samples from 54 CD patients undergoing ileocecal resection were prospectively collected before surgery and at month 1, 3 and 6 after surgery. POR - defined by a modified Rutgeerts score ≥i2b on endoscopy was assessed at month 6. The microbiota was evaluated by 16S rDNA sequencing using an Illumina MiSeq platform. Calculation of alpha and beta diversity and statistical analysis were performed in QIIME. Results: Patients developing early POR (N=23) harbored more Coriobacteriaceae, Corynebacteriaceae and Micrococcaceae in their faecal samples before surgery, than patients without recurrence (N=31) (p<0.04). During the first 3 months postoperatively, no significant taxonomic differences were observed between both patient groups. At month 6, recurrence patients had a higher relative abundance of Fusobacteria (FDR=0.09). The impact of resection on the fecal microbiome was shown by an increase of Negativicutes (FDR=0.02) and reduction of Bifidobacteriales (FDR=0.04) in all CD patients whereas recurrence patients additionally were marked by an increase of Fusobacteria (FDR=0.03) and decrease of Faecalibacterium (p=0.04). Smoking (N=16) was not associated with early POR in this cohort, but smoking did impact on the fecal microbiota. Alpha diversity was significantly reduced in active smokers at baseline (p=0.028), month 3 (p=0.016) and month 6 (p=0.023) after surgery. In general, smokers were characterized by an enrichment of Veillonellaceae (FDR=0.09) and reduction of Ruminococcaceae (FDR=0.005) and Lachnospiraceae (FDR=0.03). Within these families, the relative abundance of essential types of butyrate and other short-chain fatty acids-producing bacteria such as Faecalibacterium, Roseburia, Dorea, Coprococcus, Blautia and Ruminococcus were depleted. Conclusions: Ileocecal resection has an impact on the fecal microbiota composition which mostly affects members of Negativicutes and Bifidobacteriales. The microbial differences between patients developing recurrence and patients remaining in remission are minor during the first 3 months whereas early recurrence at month 6 was mainly associated with an enrichment of Fusobacteria. Although smoking was not associated with early POR, it did show a significant impact on the microbial composition which might have potential implications at later stages of the disease.

The Fus1 gene resides in the critical 3p21.3 human chromosomal region deleted in lung and breast cancers. Recently, the tumour suppressor properties of Fus1 were confirmed experimentally by intra‐tumoural administration of Fus1 that suppressed experimental lung metastasis in mice. We generated Fus1 ‐deficient mice that were viable, fertile, and demonstrated a complex immunological phenotype. Animals with a disrupted Fus1 gene developed signs of autoimmune disease, such as vasculitis, glomerulonephritis, anaemia, circulating autoantibodies, and showed an increased frequency of spontaneous vascular tumours. Preliminary analysis of immune cell populations revealed a consistent defect in NK cell maturation in Fus1 null mice that correlated with changes in the expression of IL‐15. Injection of IL‐15 into Fus1 knockout mice completely rescued the NK cell maturation defect. Based on these results, we propose the hypothesis that Fus1 deficiency affects NK cell maturation through the reduction of IL‐15 production but does not directly alter their developmental capacity. Since acquired immunity was not affected in Fus1 ‐deficient animals, we suggest a relationship between the Fus1 protein and the regulation of innate immunity via IL‐15 production. The increased frequency of spontaneous cancers and the development of an autoimmune syndrome in Fus1 null mice imply that these mice could serve as a model for studying molecular mechanisms of anti‐tumour immunity and autoimmunity. Published in 2007 by John Wiley & Sons, Ltd.

We have characterized the heterogeneity of human blood NK cell subsets defined by expression of KIR, lectin like receptors and NK cell differentiation markers within a cohort of 51 healthy Caucasian individuals. High inter-individual variability in cell surface expression of most NK cell markers is observed. Range values defining NK cell subsets in healthy donors were further used as references to characterize 14 patients with NK-type lymphoproliferative disease of granular lymphocytes (NK-LDGL). Alterations of the KIR repertoire were noted in all NK-LDGL patients. NK cell expansions were classified as oligoclonal KIR(+) or as non-detectable KIR ((nd)KIR) using anti-KIR2DL1/2DS1, anti-KIR2DL2/2DL3/2DS2, anti-KIR3DL1 and anti-KIR2DS4 monoclonal antibodies. A major reduction in the size of the CD56(bright) NK cell subset was a constant feature of NK-LDGL. Altered distribution of CD94(+), CD161(+), and CD162R(+) NK cell subsets was also observed in NK-LDGL patients. Considering the potential role of NK cells in eliminating tumors or virus-infected cells, the reference values defined in this study should be valuable to characterize both quantitative and qualitative alterations of the NK cell repertoire in pathological conditions and to monitor NK cell reconstitution following hematopoietic transplantation.

Objective. To describe a novel syndrome characterized by severe prenatal and postnatal growth failure, mild skeletal and facial abnormalities, and primary immunodeficiency.Design. The syndrome was observed in 2 sisters. The elder child died of cytomegalovirus infection when she was 18 months old, whereas the younger sister is doing well at 5 years old. We report here clinical, hematologic, and immunologic data for both sisters and compare them with all known inherited disorders with similar clinical or immunologic features.Results. The immune defect consists of a lack of detectable natural killer cells and small numbers of CD8 alphabeta T cells and polymorphonuclear neutrophils. This is the first report of prenatal and postnatal growth failure associated with mild skeletal and facial abnormalities and primary immunodeficiency.Conclusion. This novel syndrome probably is caused by an autosomal recessive gene defect impairing both intrauterine growth and natural killer cell development. The identification of other kindreds with this syndrome would facilitate the search for its genetic basis.

We retrospectively analyzed the percentages and absolute numbers of T cells, natural killer (NK) cells and NK cell subsets in cryopreserved samples of either bone marrow or blood non-T cell-depleted allogeneic MHC-matched hematopoietic grafts. Using flow cytometry, we found higher numbers of NK cells in aphereses than in bone marrow collections. We further investigated the distribution of NK cell subsets, defined by the cell surface expression of MHC class I-specific receptors, in these allogeneic grafts. The distribution of NK cell subsets from the two different origins were similar, with the exception of the CD158a/h(+) NK cell subset, whose size appeared to be smaller in bone marrow. The search for relations between the numbers of infused cells and post-transplantation events demonstrated that increasing numbers of infused T cells but not NK cells are related with decreased overall survival. Our study highlights the toxicity of infused T cells but not NK cells in allogeneic MHC-matched hematopoietic grafts. These data pave the way for further trials to investigate the effect of NK cell infusion in MHC-matched allogeneic transplantation, and in particular whether ex vivo NK cell expansion and activation may enhance the anti-tumoral effect of the procedure and decrease its morbidity.

Engagement of inhibitory natural killer (NK) cell receptors for MHC class I molecules (NKR) can impair NK-cell activation programs. Inhibitory NKR thus confer to NK cells the capacity to discriminate between MHC class I+ and MHC class I- target cells, and are therefore involved in the control of NK-cell tolerance to self, as well as in the elimination of MHC class I- distressed cells by NK cells. In human and mouse, a subset of alpha beta T cells also express inhibitory NKR at their surface, but the biological function of inhibitory NKR on T cells remains to be precisely elucidated. We refer to these cells as T memory type 1 (Tm1) cells, and review here the phenotypic and functional features of this subset of memory-phenotype CD8(+) alpha beta T cells. in vitro studies suggest that inhibitory NKR are involved in the peripheral control of T-cell self-tolerance. In vitro and in vivo analysis have revealed a novel biological function for inhibitory NKR when expressed on T cells. Indeed, engagement of inhibitory NKR on T cells provides them with survival signals against activation-induced cell death. Thus, sensing of self-MHC class I molecules by inhibitory NKR displayed on alpha beta T cells leads to the in vivo accumulation of Tm 1 cells.

ITIM-bearing NK receptors for MHC class I molecules (NKR) can impair NK cell activation programs and confer to NK cells the capacity to discriminate between MHC class I+ and MHC class I− target cells. Inhibitory NKR are thus involved in the control of NK tolerance to self. A subset of T cells also express inhibitory NKR at the cell surface. We refer to these cells as Tml cells (T memory type 1 cells), and describe here the phenotypic and functional features of this subset of memory-phenotype CD8+ T cells. This analysis reveals a novel biological function for inhibitory NKR when expressed on T cells. Indeed, sensing of self-MHC class I molecules by inhibitory NKR displayed on T cell surface leads to the in vivo accumulation of Tml cells.