Whereas humanized mouse models have contributed significantly to human immunology research, human T cells developing in mouse thymic environment fail to demonstrate HLA-restricted function. To achieve HLA-restricted human immune response, we created an immune-compromised non-obese diabetic/SCID/IL2rg null strain (NSG) with homozygous expression of HLA class I heavy chain and light chain (NSG-HLA-A2/HHD). Transplantation of purified Lin−CD34+ CD38− human hematopoietic stem cells into NSG-HLA-A2/HHD newborns resulted in the development of human CD4+ and CD8+ TCRαβ+ T cells and CD4−CD8− and CD8+ TCRγδ+ cells in recipient bone marrow and spleen. Human cytotoxic T lymphocytes (CTLs) become functionally mature, as evidenced by the production of granzyme corresponding to phenotypic transition from naïve to effector memory CTLs. In these recipients, human Th17 cells developed along with Th1 and Th2 cells. Epstein-Barr virus (EBV) infection in the humanized NSG-HLA-A2/HHD recipients resulted in the formation of lymphoproliferative lesions consisting mainly of human B cells with scattered human T cells. Human CTLs developing in the recipients recognized EBV-derived peptides in an HLArestricted manner and exerted HLA-restricted cytotoxicity against EBV-infected human B cells. The HLA-expressing humanized mouse with functional HLA-restricted T cells and consistent representation of rare T-cell subsets overcomes a major constraint in human immunology, and serves as a useful model for investigation of human immune responses against pathogens and for the development of therapeutic strategies against human diseases.human immunology | T-cell development | HLA restriction | Epstein-Barr virus

Human acute myeloid leukemia (AML) originates from rare leukemia stem cells (LSCs). Because these chemotherapy-resistant LSCs are thought to underlie disease relapse, effective therapeutic strategies specifically targeting these cells may be beneficial. Here, we report identification of a primary human LSC gene signature and functional characterization of human LSC-specific molecules in vivo in a mouse xenotransplantation model. In 32 of 61 (53%) patients with AML, either CD32 or CD25 or both were highly expressed in LSCs. CD32-or CD25-positive LSCs could initiate AML and were cell cycle-quiescent and chemotherapy-resistant in vivo. Normal human hematopoietic stem cells depleted of CD32-and CD25-positive cells maintained long-term multilineage hematopoietic reconstitution capacity in vivo, indicating the potential safety of treatments targeting these molecules. In addition to CD32 and CD25, quiescent LSCs within the bone marrow niche also expressed the transcription factor WT1 and the kinase HCK. These molecules are also promising targets for LSC-specific therapy.

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Key Points FMT was safely performed in SCT patients, with 3 complete responses and 1 partial response. Temporal microbiota dynamics seem linked to gut condition and effector regulatory T cells also increased during response to FMT.

Leptin-deficient ob/ob mice show many characteristics of obesity, including excess peripheral adiposity as well as severe hepatic steatosis, at least in part, due to increased hepatic lipogenesis. Polyunsaturated fatty acids (PUFAs) are not only ligands for peroxisome proliferator-activated receptor (PPAR) ␣ but are also negative regulators of hepatic lipogenesis, which is thought to be mediated by the repression of sterol regulatory element-binding protein ( S terol regulatory element-binding proteins (SREBPs) are members of the basic helix-loop-helix leucine zipper family of transcription factors that regulate fatty acid and cholesterol synthesis (reviewed in Brown and Goldstein 1 ). Unlike other members of the family, SREBPs are synthesized as precursors bound to the endoplasmic reticulum and nuclear envelope and are released from the membrane into the nucleus as mature proteins by cleavage processes. To date, 3 isoforms of SREBP, -1a, -1c, and -2, have been identified and characterized. The predominant SREBP-1 isoform in liver and adipose tissue is SREBP-1c. Whereas SREBP-2 plays a crucial role in regulation of cholesterol synthesis, SREBP-1c controls the transcription and expression of lipogenic enzymes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1) (reviewed in Shimano 2 and Horton et al. 3 ). It is remarkable that SREBP-1c regulates not only the synthetic rate of triglycerides but also the amount of their storage in the liver. 4,5 Thus, SREBP-1 has been revealed to be a promising target for hepatic steatosis (fatty livers) from a therapeutic point of view.The leptin-deficient ob/ob mouse model of obesity exhibits severe obesity and obesity-related symptoms, including hepatic steatosis and insulin resistance (reviewed in Bray and York 6 ). The livers of ob/ob mice have an increase in triglyceride content, probably because of the increased lipogenesis paralleled by elevated messenger RNA (mRNA) expression and enzymatic activity of several lipogenic enzymes such as FAS and SCD1. 6,7 Recently, it has been reported that both SREBP-1c mRNA and its active nuclear protein are increased in ob/ob mouse livers. 8 Furthermore, we have demonstrated in a previous report 5 that the disruption of the SREBP-1 gene in ob/ob mice leads to marked amelioration of hepatic steatosis.Dietary polyunsaturated fatty acids (PUFAs) of the n-6 and n-3 families are well established as negative regulators of hepatic lipogenesis (reviewed in Clark and Jump 9 ). Recently, others and we have shown that the suppressive