Metformin, a prescribed drug for type 2 diabetes, has been reported to have anti-cancer effects; however, the underlying mechanism is poorly understood. Here we show that this mechanism may be immune-mediated. Metformin enabled normal but not T-cell-deficient SCID mice to reject solid tumors. In addition, it increased the number of CD8 + tumor-infiltrating lymphocytes (TILs) and protected them from apoptosis and exhaustion characterized by decreased production of IL-2, TNFα, and IFNγ. CD8 + TILs capable of producing multiple cytokines were mainly PD-1 − Tim-3 + , an effector memory subset responsible for tumor rejection. Combined use of metformin and cancer vaccine improved CD8 + TIL multifunctionality. The adoptive transfer of antigen-specific CD8 + T cells treated with metformin concentrations as low as 10 μM showed efficient migration into tumors while maintaining multifunctionality in a manner sensitive to the AMP-activated protein kinase (AMPK) inhibitor compound C. Therefore, a direct effect of metformin on CD8 + T cells is critical for protection against the inevitable functional exhaustion in the tumor microenvironment.immune exhaustion | CD8T cells | antitumor immunity | tumor microenvironment | multifunctionality

IgM is the first antibody to be produced in a humoral immune response and plays an important role in the primary stages of immunity. Here we describe a mouse Fc receptor, designated Fc alpha/microR, and its human homolog, that bind both IgM and IgA with intermediate or high affinity. Fc alpha/microR is constitutively expressed on the majority of B lymphocytes and macrophages. Cross-linking Fc alpha/microR expressed on a pro-B cell line Ba/F3 transfectant with soluble IgM or IgM-coated microparticles induced internalization of the receptor. Fc alpha/microR also mediated primary B lymphocyte endocytosis of IgM-coated Staphylococcus aureus. Thus, Fc alpha/microR is involved in the primary stages of the immune response to microbes.

Whereas ligation of the DNAM-1 adhesion molecule triggers cytotoxicity mediated by normal NK and T cells, this function was defective in NK cell clones from leukocyte adhesion deficiency syndrome. However, genetic reconstitution of cell surface expression of LFA-1 restored the ability of DNAM-1 to initiate anti-DNAM-1 mAb-induced cytotoxicity, indicating a functional relationship between DNAM-1 and LFA-1. Further studies demonstrated that LFA-1 physically associates with DNAM-1 in NK cells and anti-CD3 mAb stimulated T cells, for which serine phosphorylation of DNAM-1 plays a critical role. In addition, cross-linking of LFA-1 induces tyrosine phosphorylation of DNAM-1, for which the Fyn protein tyrosine kinase is responsible. These results indicate that DNAM-1 is involved in the LFA-1-mediated intracellular signals.

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Among 380 Mycoplasma pneumoniae isolates from 3,678 pediatric patients with community-acquired pneumonia, 50 macrolide-resistant strains had an A2063G transition in domain V of the 23S rRNA, whereas 5 had an A2064G transition. These resistant strains increased rapidly from April 2002 to December 2006.For Mycoplasma pneumoniae, a major etiologic agent of lower respiratory tract infections acquired in the community, 14-membered ring macrolides (ML) generally are recognized as first-choice agents. In Japan, ML-resistant (ML r ) M. pneumoniae possessing a 23S rRNA mutation first was isolated from pediatric patients with community-acquired pneumonia (CAP) and bronchitis as reported in 2001 by Okazaki et al. (4). Patient symptoms appeared to be prolonged when isolates showed ML resistance (5).We subjected M. pneumoniae isolated from pediatric patients with CAP between 2002 and 2006 to susceptibility evaluation for eight agents, including ML. In strains showing ML resistance, the 23S rRNA gene was analyzed.Between April 2002 and December 2006, 3,678 clinical samples were sent to our laboratory from pediatricians affiliated with 10 institutions participating in the Acute Respiratory Diseases Study Group. All samples originating from pediatric patients diagnosed with pneumonia according to clinical symptoms and chest X-ray images were collected after informed consent was given by the patients and/or their parents or guardians.Immediately after receipt, the samples were suspended in 1.5 ml of pleuropneumonia-like organism (PPLO) broth (Difco, Detroit, MI). DNA then was extracted by using Extragen II (Tosoh, Tokyo, Japan) according to the manufacturer's protocol. Real-time PCR to detect M. pneumoniae was performed as described previously (2) using the extracted DNA. Culture of M. pneumoniae was carried out for PCR-positive samples using PPLO broth according to previously described methods (6).The MICs of eight agents for M. pneumoniae isolates were determined with microdilution methods using PPLO broth.These agents were erythromycin, clarithromycin, azithromycin, josamycin, rokitamycin, telithromycin, minocycline, and levofloxacin. M. pneumoniae M129 strain was used as a control.The full length of the 23S rRNA gene was sequenced by methods described previously (3) in 55 M. pneumoniae strains showing ML resistance.For patients with adequate clinical information, clinical courses of CAP caused by ML r M. pneumoniae (n ϭ 53) were compared to those of CAP with ML-susceptible (ML s ) M. pneumoniae (n ϭ 58). Variables compared included (i) the number of days from initiation of ML treatment until defervescence to 37°C and (ii) whether or not initial treatment with ML was changed later to another agent. Body temperature that exceeded 38°C at least once daily was defined as ongoing fever. Table 1 Table 2 shows the MIC range, MIC 50 , and MIC 90 for eight agents according to the presence or absence of a mutation of the 23S rRNA gene in the 380 M. pneumoniae isolates; 50 strains had an A2063G transition in domain V, and 5 strains had...