Summary Description of macrophage activation is currently contentious and confusing. Like the biblical Tower of Babel, macrophage activation encompasses a panoply of descriptors used in different ways. The lack of consensus on how to define macrophage activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only the two types of activated macrophages often termed M1 and M2. Here we describe a set of standards for the field encompassing three principles: the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation, with the goal of unifying experimental standards for diverse experimental scenarios. Collectively, we propose a common framework for macrophage activation nomenclature.

SummaryMacrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease.

Arabidopsis thaliana ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1) controls defense activation and programmed cell death conditioned by intracellular Toll-related immune receptors that recognize specific pathogen effectors. EDS1 is also needed for basal resistance to invasive pathogens by restricting the progression of disease. In both responses, EDS1, assisted by its interacting partner, PHYTOALEXIN-DEFICIENT4 (PAD4), regulates accumulation of the phenolic defense molecule salicylic acid (SA) and other as yet unidentified signal intermediates. An Arabidopsis whole genome microarray experiment was designed to identify genes whose expression depends on EDS1 and PAD4, irrespective of local SA accumulation, and potential candidates of an SA-independent branch of EDS1 defense were found. We define two new immune regulators through analysis of corresponding Arabidopsis loss-of-function insertion mutants. FLAVIN-DEPENDENT MONOOXYGENASE1 (FMO1) positively regulates the EDS1 pathway, and one member (NUDT7) of a family of cytosolic Nudix hydrolases exerts negative control of EDS1 signaling. Analysis of fmo1 and nudt7 mutants alone or in combination with sid2-1, a mutation that severely depletes pathogen-induced SA production, points to SA-independent functions of FMO1 and NUDT7 in EDS1-conditioned disease resistance and cell death. We find instead that SA antagonizes initiation of cell death and stunting of growth in nudt7 mutants.

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The discovery of tumor-associated antigens (TAA) in certain human malignancies has prompted renewed efforts to develop antigen-specific immunotherapy of cancer. However, most TAA described thus far are expressed in one or a few tumor types, and, among patients with these types of tumors, TAA expression is not universal. Here, we characterize the telomerase catalytic subunit (hTERT) as a widely expressed TAA capable of triggering antitumor cytotoxic T lymphocyte (CTL) responses. More than 85% of human cancers exhibit strong telomerase activity, but normal adult tissues, with few exceptions, do not. In a human system, CD8+ CTL specific for an hTERT peptide and restricted to MHC HLA-A2 lysed hTERT+ tumors from multiple histologies. These findings identify hTERT as a potentially important and widely applicable target for anticancer immunotherapeutic strategies.

Globally suppressed T-cell function has been described in many patients with cancer to be a major hurdle for the development of clinically efficient cancer immunotherapy. Inhibition of antitumor immune responses has been mainly linked to inhibitory factors present in cancer patients. More recently, increased frequencies of CD4 ؉ CD25 hi regulatory T cells (T reg cells) have been described as an additional mechanism reducing immunity. We assessed 73 patients with B-cell chronic lymphocytic leukemia ( IntroductionHuman and murine CD4 ϩ CD25 ϩ T cells contain cells that suppress antigen-specific T-cell immune responses. [1][2][3][4][5] These naturally occurring regulatory CD4 ϩ CD25 ϩ T cells originate from the thymus and play a central role in the maintenance of peripheral tolerance by suppression of autoreactive T-cell populations. In murine models, regulatory T cells (T reg cells) prevent autoimmune and inflammatory diseases 1,6,7 and inhibit antitumor immune responses. [8][9][10][11][12] Although a truly unique marker for T reg cells is still not available, several molecules have been associated with these cells including cytotoxic T lymphocyte-associated protein 4 (CTLA4), [13][14][15][16] glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR, TNFRSF18), 17,18 Forkhead box P3 (FOXP3), [19][20][21] Lselectin (CD62L, SELL), 22,23 and OX40 antigen (CD134, TNFRSF4). 23,24 In humans, T reg cells are enriched within the CD4 ϩ CD25 hi population, whereas CD4 ϩ CD25 lo T cells represent mainly previously activated T helper cells. 25 These CD4 ϩ CD25 hi T reg cells inhibit proliferation and cytokine release by conventional CD4 ϩ CD25 Ϫ T cells. 26 Decrease of these cells was found in patients with autoimmune diseases, 27-31 whereas an increase of T reg cells in patients after allogeneic bone marrow transplantation was associated with a reduced graft-versus-host disease. [32][33][34][35] In patients with malignant melanoma, 36 Hodgkin lymphoma, 37 or ovarian, 38,39 gastric, 40,41 lung, 39,42 breast, 43,44 and pancreatic cancer 43 inhibitory CD4 ϩ CD25 ϩ T cells are also increased. In an elegant study, Curiel et al 38 demonstrated that functional T reg cells were enriched in ascites from women with ovarian cancer, migrated toward CCL22 expressed by tumor cells and tumor-associated macrophages, and specifically inhibited antitumor immunity. Moreover, within this setting, the increase of T reg cells predicted poor survival. 38 Only recently, studies assessing a potential influence of chemotherapy on T reg cells have been initiated. In mice, low-dose cyclophosphamide decreased the number of T reg cells. 45 Based on these observations we were interested in understanding whether CD4 ϩ CD25 hi T cells are also increased and possess inhibitory capacities in B-cell chronic lymphocytic leukemia (CLL) and, if so, to assess the frequency and function in the context of stage of disease and prior therapy. CLL, the most common type of leukemia in the Western hemisphere, 46 is characterized by clonal proliferat...

Multiple clinical trials have shown the efficacy of adoptively transferred allogeneic antigen-specific T cells for the treatment of viral infections and relapsed hematologic malignancies. In contrast, the therapeutic potential of autologous antigen-specific T cells has yet to be established since it has been technically difficult to generate sufficient numbers of these T cells, ex vivo. A major obstacle to the success of this objective derives from our inability to simply and rapidly isolate and/or expand large numbers of highly efficient antigen presenting cells (

The innate immune system represents an ancient host defence mechanism that protects against invading microorganisms. An important class of immune effector molecules to fight pathogen infections are antimicrobial peptides (AMPs) that are produced in plants and animals. In Drosophila, the induction of AMPs in response to infection is regulated through the activation of the evolutionarily conserved Toll and immune deficiency (IMD) pathways. Here we show that AMP activation can be achieved independently of these immunoregulatory pathways by the transcription factor FOXO, a key regulator of stress resistance, metabolism and ageing. In non-infected animals, AMP genes are activated in response to nuclear FOXO activity when induced by starvation, using insulin signalling mutants, or by applying small molecule inhibitors. AMP induction is lost in foxo null mutants but enhanced when FOXO is overexpressed. Expression of AMP genes in response to FOXO activity can also be triggered in animals unable to respond to immune challenges due to defects in both the Toll and IMD pathways. Molecular experiments at the Drosomycin promoter indicate that FOXO directly binds to its regulatory region, thereby inducing its transcription. In vivo studies in Drosophila, but also studies in human lung, gut, kidney and skin cells indicate that a FOXO-dependent regulation of AMPs is evolutionarily conserved. Our results indicate a new mechanism of cross-regulation of metabolism and innate immunity by which AMP genes can be activated under normal physiological conditions in response to the oscillating energy status of cells and tissues. This regulation seems to be independent of the pathogen-responsive innate immunity pathways whose activation is often associated with tissue damage and repair. The sparse production of AMPs in epithelial tissues in response to FOXO may help modulating the defence reaction without harming the host tissues, in particular when animals are suffering from energy shortage or stress.