Advances in Immunology最新文献

A20/TNFAIP3 is a TNF induced gene that plays a profound role in preserving cellular and organismal homeostasis (Lee, et al., 2000; Opipari etal., 1990). This protein has been linked to multiple human diseases via genetic, epigenetic, and an emerging series of patients with mono-allelic coding mutations. Diverse cellular functions of this pleiotropically expressed protein include immune-suppressive, anti-inflammatory, and cell protective functions. The A20 protein regulates ubiquitin dependent cell signals; however, the biochemical mechanisms by which it performs these functions is surprisingly complex. Deciphering these cellular and biochemical facets of A20 dependent biology should greatly improve our understanding of murine and human disease pathophysiology as well as unveil new mechanisms of cell and tissue biology.

Dendritic cells are a specialized subset of hematopoietic cells essential for mounting immunity against tumors and infectious disease as well as inducing tolerance for maintenance of homeostasis. DCs are equipped with number of immunoregulatory or stimulatory molecules that interact with other leukocytes to modulate their functions. Recent advances in DC biology identified a specific role for the conventional dendritic cell type 1 (cDC1) in eliciting cytotoxic CD8+ T cells essential for clearance of tumors and infected cells. The critical role of this subset in eliciting immune responses or inducing tolerance has largely been defined in mice whereas the biology of human cDC1 is poorly characterized owing to their extremely low frequency in tissues. A detailed characterization of the functions of many immunoregulatory and stimulatory molecules expressed by human cDC1 is critical for understanding their biology to exploit this subset for designing novel therapeutic modalities against cancer, infectious disease and autoimmune disorders.

The NLRP3 inflammasome is a cytoplasmic multiprotein complex, the assembly of which can be initiated in response to various exogenous or endogenous danger signals. Excessive activation of the NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of human inflammatory diseases, suggesting that the NLRP3 inflammasome is a potential target for the treatment of these diseases. However, clinical drugs targeting the NLRP3 inflammasome are still not available. Recent data have elucidated the different signaling pathways or events that can control NLRP3 inflammasome activation and have provided some potential compounds with anti-NLRP3 inflammasome activity. Here, we summarize the molecular mechanisms and diseases involved in NLRP3 inflammasome activation and discuss the potential strategies targeting different aspects of the NLRP3 inflammasome and its implications for the treatment of inflammatory diseases.

Seven members of signaling lymphocytic activation molecule (SLAM) family receptors (SFRs) are ubiquitously expressed on hematopoietic cells and they play critical roles in immune cell differentiation and activation. The engagement of these receptors transmits intracellular signaling mainly by recruiting SLAM-associated protein (SAP) and its related adaptors, EWS-FLI1-activated transcript-2 (EAT-2) and EAT-2-related transducer (ERT). The critical roles of SFRs and SAP-family adaptors are highlighted by the discovery that SAP is mutated in human X-linked lymphoproliferative (XLP1) disease in which the contact between T and B cells in germinal center and cytotoxic lymphocytes (NK cells and CD8⁺ T cells) function are severely compromised. These immune defects are closely associated with the defective antibody production and the high incidence of lymphoma in the patients with XLP1. In addition to these well-known functions, SLAM-SAP family is involved in NK cell education, a process describing NK cell functional competence. In this chapter, we will mainly discuss these unappreciated roles of SAP-dependent and SAP-independent SFR signaling in regulating MHC-I-independent NK cell education.

Metals are essential components in all forms of life required for the function of nearly half of all enzymes and are critically involved in virtually all fundamental biological processes. Especially, the transition metals iron (Fe), zinc (Zn), manganese (Mn), nickel (Ni), copper (Cu) and cobalt (Co) are crucial micronutrients known to play vital roles in metabolism as well due to their unique redox properties. Metals carry out three major functions within metalloproteins: to provide structural support, to serve as enzymatic cofactors, and to mediate electron transportation. Metal ions are also involved in the immune system from metal allergies to nutritional immunity. Within the past decade, much attention has been drawn to the roles of metal ions in the immune system, since increasing evidence has mounted to suggest that metals are critically implicated in regulating both the innate immune sensing of and the host defense against invading pathogens. The importance of ions in immunity is also evidenced by the identification of various immunodeficiencies in patients with mutations in ion channels and transporters. In addition, cancer immunotherapy has recently been conclusively demonstrated to be effective and important for future tumor treatment, although only a small percentage of cancer patients respond to immunotherapy because of inadequate immune activation. Importantly, metal ion-activated immunotherapy is becoming an effective and potential way in tumor therapy for better clinical application. Nevertheless, we are still in a primary stage of discovering the diverse immunological functions of ions and mechanistically understanding the roles of these ions in immune regulation. This review summarizes recent advances in the understanding of metal-controlled immunity. Particular emphasis is put on the mechanisms of innate immune stimulation and T cell activation by the essential metal ions like calcium (Ca²⁺), zinc (Zn²⁺), manganese (Mn²⁺), iron (Fe²⁺/Fe³⁺), and potassium (K⁺), followed by a few unessential metals, in order to draw a general diagram of metalloimmunology.

Natural killer (NK) cells are innate immune cells critically involved in the control of cancer. Their important role in cancer immunity reflects the ability of NK cells to recognize malignant cells through an array of germline-encoded receptors expressed on their surface, enabling NK cells to detect and rapidly kill tumor cells through targeted cytotoxicity. In addition to their cytotoxic activity, NK cells fulfill a fundamental and often underappreciated role in the local orchestration of cancer immunity through their ability to communicate with innate and adaptive immune cells within the tumor microenvironment (TME), which is achieved through the secretion of multiple chemokines, cytokines, and growth factors. Within tumor tissue, NK cells regulate the recruitment, survival and functional activity of various immune cells including monocytes, granulocytes, dendritic cells and T cells, thereby shaping intratumoral immune cell composition and functionality. Emerging evidence further suggest a role of NK cells in the regulation of stromal cells within the TME. Here, we discuss key aspects of NK cell communication with other intratumoral cell types and its role for cancer immunity. Strategies aimed at boosting anti-cancer immunity by enhancing NK cell communication and functionality within tumor tissue provide attractive new ways for treatment of cancer patients.

Phosphoinositide 3-kinase delta (PI3Kδ) mediates signaling transduction downstream of diverse immune receptors, including the T cell receptor (TCR), the B cell receptor (BCR), costimulatory molecules and cytokine receptors. Our understanding of the role of PI3Kδ in the immune system comes primarily from mice, and especially from the consequences of pharmacological inhibition of PI3Kδ in mouse models of human disease as well as the consequences of genetic manipulation, resulting in hyperactivation or loss of PI3Kδ function. In case of humans, in vitro studies with PI3Kδ-specific inhibitors, the consequences of treatment of hematologic malignancies with the PI3Kδ-specific inhibitor idelalisib and primary immunodeficiency disorders due to germline variants hyper- or underactivating PI3Kδ provide most of our knowledge on the role of PI3Kδ in immunity and immune regulation. In this review, we summarize the physiological and pathophysiological roles of PI3Kδ in the human immune system, focusing on immunodeficiency due to defects in PI3Kδ signaling and especially on the recently reported cases with mutations resulting in loss of PI3Kδ activity.