Opportunities for Treg cell therapy for the treatment of human disease

Regulatory T (Treg) cells are essential for maintaining peripheral tolerance, preventing autoimmunity, and limiting chronic inflammatory diseases. This small CD4+ T cell population can develop in the thymus and in the peripheral tissues of the immune system through the expression of an epigenetically stabilized transcription factor, FOXP3. Treg cells mediate their tolerogenic effects using multiple modes of action, including the production of inhibitory cytokines, cytokine starvation of T effector (e.g., IL-2), Teff suppression by metabolic disruption, and modulation of antigen-presenting cell maturation or function. These activities together result in the broad control of various immune cell subsets, leading to the suppression of cell activation/expansion and effector functions. Moreover, these cells can facilitate tissue repair to complement their suppressive effects. In recent years, there has been an effort to harness Treg cells as a new therapeutic approach to treat autoimmune and other immunological diseases and, importantly, to re-establish tolerance. Recent synthetic biological advances have enabled the cells to be genetically engineered to achieve tolerance and antigen-specific immune suppression by increasing their specific activity, stability, and efficacy. These cells are now being tested in clinical trials. In this review, we highlight both the advances and the challenges in this arena, focusing on the efforts to develop this new pillar of medicine to treat and cure a variety of diseases

A point mutation in the murine Hem1 gene reveals an essential role for Hematopoietic Protein 1 in lymphopoiesis and innate immunity

Hem1 (Hematopoietic protein 1) is a hematopoietic cell-specific member of the Hem family of cytoplasmic adaptor proteins. Orthologues of Hem1 in Dictyostelium discoideum, Drosophila melanogaster, and Caenorhabditis elegans are essential for cytoskeletal reorganization, embryonic cell migration, and morphogenesis. However, the in vivo functions of mammalian Hem1 are not known. Using a chemical mutagenesis strategy in mice to identify novel genes involved in immune cell functions, we positionally cloned a nonsense mutation in the Hem1 gene. Hem1 deficiency results in defective F-actin polymerization and actin capping in lymphocytes and neutrophils caused by loss of the Rac-controlled actin-regulatory WAVE protein complex. T cell development is disrupted in Hem1-deficient mice at the CD4−CD8− (double negative) to CD4+CD8+ (double positive) cell stages, whereas T cell activation and adhesion are impaired. Hem1-deficient neutrophils fail to migrate in response to chemotactic agents and are deficient in their ability to phagocytose bacteria. Remarkably, some Rac-dependent functions, such as Th1 differentiation and nuclear factor κB (NF-κB)–dependent transcription of proinflammatory cytokines proceed normally in Hem1-deficient mice, whereas the production of Th17 cells are enhanced. These results demonstrate that Hem1 is essential for hematopoietic cell development, function, and homeostasis by controlling a distinct pathway leading to cytoskeletal reorganization, whereas NF-κB–dependent transcription proceeds independently of Hem1 and F-actin polymerization

Recent advances in immunotherapies: from infection and autoimmunity, to cancer, and back again

Abstract For at least 300 years the immune system has been targeted to improve human health. Decades of work advancing immunotherapies against infection and autoimmunity paved the way for the current explosion in cancer immunotherapies. Pathways targeted for therapeutic intervention in autoimmune diseases can be modulated in the opposite sense in malignancy and infectious disease. We discuss the basic principles of the immune response, how these are co-opted in chronic infection and malignancy, and how these can be harnessed to treat disease. T cells are at the center of immunotherapy. We consider the complexity of T cell functional subsets, differentiation states, and extrinsic and intrinsic influences in the design, success, and lessons from immunotherapies. The integral role of checkpoints in the immune response is highlighted by the rapid advances in FDA approvals and the use of therapeutics that target the CTLA-4 and PD-1/PD-L1 pathways. We discuss the distinct and overlapping mechanisms of CTLA-4 and PD-1 and how these can be translated to combination immunotherapy treatments. Finally, we discuss how the successes and challenges in cancer immunotherapies, such as the collateral damage of immune-related adverse events following checkpoint inhibition, are informing treatment of autoimmunity, infection, and malignancy