Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities—host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other ‘shades’ of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

During the past several decades, there has been a steady increase in the frequency of opportunistic invasive fungal infections (IFIs) in immunocompromised patients. However, there is substantial controversy concerning optimal diagnostic criteria for these IFIs. Therefore, members of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group formed a consensus committee to develop standard definitions for IFIs for clinical research. On the basis of a review of literature and an international consensus, a set of research-oriented definitions for the IFIs most often seen and studied in immunocompromised patients with cancer is proposed. Three levels of probability are proposed: "proven," "probable," and "possible." The definitions are intended for use in the context of clinical and/or epidemiological research, not for clinical decision making.

We generated three populations of macrophages (Mφ) in vitro and characterized each. Classically activated Mφ (Ca-Mφ) were primed with IFN-γ and stimulated with LPS. Type II-activated Mφ (Mφ-II) were similarly primed but stimulated with LPS plus immune complexes. Alternatively activated Mφ (AA-Mφ) were primed overnight with IL-4. Here, we present a side-by-side comparison of the three cell types. We focus primarily on differences between Mφ-II and AA-Mφ, as both have been classified as M2 Mφ, distinct from Ca-Mφ. We show that Mφ-II more closely resemble Ca-Mφ than they are to AA-Mφ. Mφ-II and Ca-Mφ, but not AA-Mφ, produce high levels of NO and have low arginase activity. AA-Mφ express FIZZ1, whereas neither Mφ-II nor Ca-Mφ do. Mφ-II and Ca-Mφ express relatively high levels of CD86, whereas AA-Mφ are virtually devoid of this costimulatory molecule. Ca-Mφ and Mφ-II are efficient APC, whereas AA-Mφ fail to stimulate efficient T cell proliferation. The differences between Ca-Mφ and Mφ-II are more subtle. Ca-Mφ produce IL-12 and give rise to Th1 cells, whereas Mφ-II produce high levels of IL-10 and thus, give rise to Th2 cells secreting IL-4 and IL-10. Mφ-II express two markers that may be used to identify them in tissue. These are sphingosine kinase-1 and LIGHT (TNF superfamily 14). Thus, Ca-Mφ, M-II, and AA-Mφ represent three populations of cells with different biological functions.

NF-B/Rel is a family of transcription factors whose activation has long been linked to the production of inflammatory cytokines. Here, we studied NF-B signaling in the regulation of the anti-inflammatory cytokine, interleukin-10 (IL-10). We identified a role for a single NF-B family member, NF-B1 (p50), in promoting the transcription of IL-10. The NF-B ciselement on IL-10 proximal promoter was located to ؊55/؊46, where p50 can homodimerize and form a complex with the transcriptional co-activator CREB-binding protein to activate transcription. The other Rel family members appear to play a negligible role in IL-10 transcription. Mice lacking p50 were more susceptible to lethal endotoxemia, and macrophages taken from p50 ؊/؊ mice exhibit skewed cytokine responses to lipopolysaccharide, characterized by decreased IL-10 and increased tumor necrosis factor and IL-12. Taken together, our studies demonstrate that NF-B1 (p50) homodimers can be transcriptional activators of IL-10. The reciprocal regulation of pro-and antiinflammatory cytokine production by NF-B1 (p50) may provide potential new ways to manipulate the innate immune response.

GARP/LRRC32 has previously been defined as a marker of activated human regulatory T-cells (Tregs) that is responsible for surface localization of latent TGF-β1. We find that GARP and latent TGF-β1 are also found on mouse Tregs activated via TCR stimulation, but in contrast to human Tregs, GARP is also expressed at a low level on resting Tregs. The expression of GARP can be upregulated on mouse Tregs by IL-2 or IL-4 exposure in the absence of TCR signaling. GARP is expressed at a low level on Tregs within the thymus and Treg precursors from the thymus concomitantly express GARP and Foxp3 upon exposure to IL-2. The expression of GARP is independent of TGF-β1 and TGF-β1 loading into GARP and is independent of furin-mediated processing of pro-TGF-β1 to latent TGF-β1. Specific deletion of GARP in CD4+ T cells results in lack of expression of latent-TGF-β1 on activated Tregs. GARP-deficient Tregs develop normally, are present in normal numbers in peripheral tissues, and are fully competent suppressors of the activation of T conventional cells in vitro. Activated Tregs expressing GARP/latent-TGF-β1 complexes are potent inducers of Th17 differentiation in the presence of exogenous IL-6 and inducers of Treg in the presence of IL-2. Induction of both Th17 producing cells and Treg is preferentially induced by Tregs expressing the latent-TGF-β1/GARP complex on their cell surface rather than by secreted latent-TGF-β1.