Immunology

Arrestins are intracellular scaffolding proteins known to regulate a range of biochemical processes including G protein-coupled receptor (GPCR) desensitization, signal attenuation, receptor turnover and downstream signaling cascades. Their roles in regulation of signaling network have lately been extended to receptors outside of the GPCR family, demonstrating their roles as important scaffolding proteins in various physiological processes including proliferation, differentiation and apoptosis. Recent studies have demonstrated a critical role for arrestins in immunological processes including key functions in inflammatory signaling pathways. In this review, we provide a comprehensive analysis of the different functions of the arrestin family of proteins especially related to immunity and inflammatory diseases.

... or experimentally in vitro, and stability and function all depend on the right mix of environmental stimuli. This review focuses on the effects of cytokines, metabolites and the microbiome on Treg biology. The role of cytokines secreted by innate and adaptive immune cells in directing Treg development and shaping their function is well established. New and emerging data suggest that metabolites, such as retinoic acid, and microbial products, such as short chain fatty acids, also have a critical role in guiding the functional specialization of Tregs. Overall, the complex interaction between distinct environmental stimuli results in unique, and in some cases tissue-specific, tolerogenic environments. Understanding the conditions that favour Treg induction, accumulation and function is critical to defining the pathophysiology of many immune mediated diseases and to developing new therapeutic interventions.

While gamma delta T cell (γδTc) anticancer immunotherapies are being developed, recent reports suggest a regulatory role for γδTc tumor-infiltrating lymphocytes. This mini-review surveys available evidence, determines strengths and weaknesses thereof and suggest directions for further exploration. We focus on human γδTc, as mouse and human γδTc repertoires differ. Regulatory γδTc are defined and compared to conventional Tregs and their roles in health and disease (focusing in on cancer) are discussed. We contrast the suggested regulatory roles for γδTc in breast and colorectal cancer with their cytotoxic capabilities in other malignancies, emphasizing the context dependence of γδTc functional plasticity. Since γδTc can be induced to exhibit regulatory properties (in some cases reversible), we carefully scrutinize experimental procedures in published reports. As γδTc garner increasing interest for their therapeutic potential, it is critical that we appreciate the full extent of their role(s) and interactions with other cell types in both the circulation and the tumor microenvironment. A comprehensive understanding will enable manipulation of γδTc to improve anti-tumor efficacy and patient outcomes.

Production of active TGF-β1 is one mechanism by which human regulatory T cells (Tregs) suppress immune responses. This production is regulated by glycoprotein A repetitions predominant (GARP), a transmembrane protein present on stimulated Tregs but not on other T lymphocytes (Th and CTLs). GARP forms disulfide bonds with proTGF-β1, favors its cleavage into latent inactive TGF-β1, induces the secretion and surface presentation of GARP·latent TGF-β1 complexes, and is required for activation of the cytokine in Tregs. We explored whether additional Treg-specific protein(s) associated with GARP·TGF-β1 complexes regulate TGF-β1 production in Tregs. We searched for such proteins by yeast two-hybrid assay, using GARP as a bait to screen a human Treg cDNA library. We identified lysosomal-associated transmembrane protein 4B (LAPTM4B), which interacts with GARP in mammalian cells and is expressed at higher levels in Tregs than in Th cells. LAPTM4B decreases cleavage of proTGF-β1, secretion of soluble latent TGF-β1, and surface presentation of GARP·TGF-β1 complexes by Tregs but does not contribute to TGF-β1 activation. Therefore, LAPTM4B binds to GARP and is a negative regulator of TGF-β1 production in human Tregs. It may play a role in the control of immune responses by decreasing Treg immunosuppression.

Regulatory T-cells (Tregs) act at the interface of host and pathogen interactions in human infectious diseases. Tregs are induced by a wide range of pathogens, but distinct effects of Tregs have been demonstrated for different pathogens and in different stages of infection. Moreover, Tregs that are induced by a specific pathogen may non-specifically suppress immunity against other microbes and parasites. Thus, Treg effects need to be assessed not only in homologous but also in heterologous infections and vaccinations. Though Tregs protect the human host against excessive inflammation, they probably also increase the risk of pathogen persistence and chronic disease, and the possibility of disease reactivation later in life. Mycobacterium leprae and Mycobacterium tuberculosis, causing leprosy and tuberculosis, respectively, are among the most ancient microbes known to mankind, and are master manipulators of the immune system toward tolerance and pathogen persistence. The majority of mycobacterial infections occur in settings co-endemic for viral, parasitic, and (other) bacterial coinfections. In this paper, we discuss recent insights in the activation and activity of Tregs in human infectious diseases, with emphasis on early, late, and non-specific effects in disease, coinfections, and vaccination. We highlight mycobacterial infections as important models of modulation of host responses and vaccine-induced immunity by Tregs.

Regulatory T cells have essential roles in regulating immune responses and limiting inappropriate inflammation. Evidence now indicates that to achieve this function, regulatory T cells must be able to migrate to the most appropriate locations within both lymphoid and non-lymphoid organs. This function is achieved via the spatiotemporally controlled expression of adhesion molecules and chemokine receptors, varying according to the developmental stage of the regulatory T cell and the location and environment where they undergo activation. In this Review, we summarise information on the roles of adhesion molecules and chemokine receptors in mediating regulatory T-cell migration and function throughout the body under homeostatic and inflammatory conditions. In addition, we review recent studies that have used in vivo imaging to examine the actions of regulatory T cells in vivo, in lymph nodes, in the microvasculature and in the interstitium of peripheral organs. These studies reveal that the capacity of regulatory T cells to undergo selective migration serves a critical role in their ability to suppress immune responses. As such, the cellular and molecular requirements of regulatory T-cell migration need to be completely understood to enable the most effective use of these cells in clinical settings.