Yisong Y. Wan

Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression

The naturally occurring regulatory T cell (Tr) is the pivotal cell type that maintains self-tolerance and exerts active immune suppression. The development and function of Tr cells is controlled by Foxp3 (refs 1, 2), a lack of which results in loss of Tr cells and massive multi-organ autoimmunity in scurfy mice and IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients. It is generally thought that, through a binary mechanism, Foxp3 expression serves as an on-and-off switch to regulate positively the physiology of Tr cells; however, emerging evidence associates decreased Foxp3 expression in Tr cells with various immune disorders. We hypothesized that Foxp3 regulates Tr cell development and function in a dose-dependent, non-binary manner, and that decreased Foxp3 expression can cause immune disease. Here, by generating a mouse model in which endogenous Foxp3 gene expression is attenuated in Tr cells, we show that decreased Foxp3 expression results in the development of an aggressive autoimmune syndrome similar to that of scurfy mice, but does not affect thymic development, homeostatic expansion/maintenance or transforming-growth-factor-β-induced de novo generation of Foxp3-expressing cells. The immune-suppressive activities of T cells with attenuated Foxp3 expression were nearly abolished in vitro and in vivo, whereas their anergic properties in vitro were maintained. This was accompanied by decreased expression of Tr cell ‘signature genes’. Notably, T cells expressing decreased Foxp3 preferentially became T-helper 2 (Th2)-type effectors even in a Th1-polarizing environment. These cells instructed Th2 differentiation of conventional T cells, which contributed to the immune diseases observed in these mice. Thus, decreased Foxp3 expression causes immune disease by subverting the suppressive function of Tr cells and converting Tr cells into effector cells; these findings are important for understanding the regulation of Tr cell function and the aetiology of various human immune diseases.

Control of TH17 cells occurs in the small intestine

Interleukin (IL)-17-producing T helper cells (TH17) are a recently identified CD4+ T cell subset distinct from T helper type 1 (TH1) and T helper type 2 (TH2) cells. TH17 cells can drive antigen-specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. The factors that are needed for the generation of TH17 cells have been well characterized. However, where and how the immune system controls TH17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory TH17 cells can be redirected to and controlled in the small intestine. TH17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that TH17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory TH17 cells simultaneously acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rTH17). These results identify mechanisms limiting TH17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of TH17 cells.

Transforming Growth Factor-β and the Immune Response: Implications for Anticancer Therapy

Immune homeostasis is a delicate balance between the immune defense against foreign pathogens and suppression of the immune system to maintain self-tolerance and prevent autoimmune disease. Maintenance of this balance involves several crucial networks of cytokines and various cell types. Among these regulators, transforming growth factor-β (TGF-β) is a potent cytokine with diverse effects on hematopoietic cells. Its pivotal function within the immune system is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, and survival. In addition, TGF-β controls the initiation and resolution of inflammatory responses through the regulation of chemotaxis and activation of leukocytes in the periphery, including lymphocytes, natural killer cells, dendritic cells, macrophages, mast cells, and granulocytes. Through its pleiotropic effects on these immune cells, TGF-β prevents the development of autoimmune diseases without compromising immune responses to pathogens. However, overactivation of this pathway can lead to several immunopathologies under physiologic conditions including cancer progression, making it an attractive target for antitumor therapies. This review discusses the biological functions of TGF-β and its effects on the immune system and addresses how immunosuppression by this cytokine can promote tumorigenesis, providing the rationale for evaluating the immune-enhancing and antitumor effects of inhibiting TGF-β in cancer patients.

The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function

The kinase TAK1 is critical for innate and B cell immunity. The function of TAK1 in T cells is unclear, however. We show here that T cell–specific deletion of the gene encoding TAK1 resulted in reduced development of thymocytes, especially of regulatory T cells expressing the transcription factor Foxp3. In mature thymocytes, TAK1 was required for interleukin 7–mediated survival and T cell receptor–dependent activation of transcription factor NF-κB and the kinase Jnk. In effector T cells, TAK1 was dispensable for T cell receptor–dependent NF-κB activation and cytokine production, but was important for proliferation and activation of the kinase p38 in response to interleukins 2, 7 and 15. Thus, TAK1 is essential for the integration of T cell receptor and cytokine signals to regulate the development, survival and function of T cells.

‘Yin–Yang’ functions of transforming growth factor-β and T regulatory cells in immune regulation

Summary: Transforming growth factor‐β (TGF‐β) and forkhead box p3‐expressing T‐regulatory (Treg) cells are critical in maintaining self‐tolerance and immune homeostasis. The immune suppressive functions of TGF‐β and Treg cells are widely acknowledged and extensively studied. Nonetheless, recent studies revealed the positive roles of TGF‐β and Treg cells in shaping the immune system and the inflammatory responses. This review discusses our and others efforts in understanding the negative (Yin) as well as the positive (Yang) roles for TGF‐β and Treg cells in immune regulation.

The roles for cytokines in the generation and maintenance of regulatory T cells

Summary:  As an essential mechanism for self‐tolerance, immune suppression has attracted much attention since the discovery of suppressor T cells, now called regulatory T cells (Tregs), in the 1990s. Different types of Tregs have been described based on distinct expression patterns of surface markers and cytokines. Cytokines are not only essential for function but also important for the generation of Tregs. Interleukin‐2 (IL‐2), transforming growth factor‐β, IL‐10, and other immunoregulatory molecules have been shown to control the generation of Tregs. The presence of other types of cells, in particular antigen‐presenting cells (APCs), is critical for the generation of Tregs. Cytokines can serve as either initiators or intermediates for the interactions between APCs and Tregs. This review discusses our current knowledge of how cytokines regulate the generation and maintenance of Tregs.

How Diverse—CD4 Effector T Cells and their Functions

CD4 effector T cells, also called helper T (Th) cells, are the functional cells for executing immune functions. Balanced immune responses can only be achieved by proper regulation of the differentiation and function of Th cells. Dysregulated Th cell function often leads to inefficient clearance of pathogens and causes inflammatory diseases and autoimmunity. Since the establishment of the Th1-Th2 dogma in the 1980s, different lineages of effector T cells have been identified that not only promote but also suppress immune responses. Through years of collective efforts, much information was gained on the function and regulation of different subsets of Th cells. In this review, we attempt to sample the essence of what has been learnt in this field over the past two decades. We will discuss the classification and immunological functions of effector T cells, the determinants for effector T cell differentiation, as well as the relationship between different lineages of effector T cells.

Multi‐tasking of helper T cells

CD4 T helper cells (Th) are critical in combating pathogens and maintaining immune homeostasis. Since the establishment of the Th1–Th2 paradigm in the 1980s, many types of specialized Th cells, including Th1, Th2, Th17, Th9, follicular helper T and regulatory T, have been identified. We have become accustomed to the idea that different Th cells are ‘committed’ to their paths but recent emerging evidence suggests that under certain conditions, seemingly committed Th cells possess plasticity and may convert into other types of effector cells. In this review, we will first introduce the major sub‐types of Th cells that are involved in immune regulation. Then, we will describe in detail the inter‐convertibility of Th cells among different sub‐types under in vitro and in vivo conditions. Finally, we will discuss our current understanding of the underlying mechanisms on how a particular type of Th cells may convert into other types of Th cells.

TGF-β and Regulatory T Cell in Immunity and Autoimmunity

IntroductionThe immune response is controlled by several inhibitory mechanisms. These mechanisms include regulatory T cells, which exist in multiple classes. Notable among these are Foxp3-expressing regulatory T cells (Treg), NKT cells, and Tr1 cells. Common to these mechanisms are inhibitory cytokines such as interleukin-10 and transforming growth factor-beta (TGF-β). TGF-β and Foxp3-expressing Treg cells are critical in maintaining self-tolerance and immune homeostasis.DiscussionsThe immune suppressive functions of TGF-β and Treg cells are widely acknowledged and extensively studied. Nonetheless, recent studies revealed the positive roles for TGF-β and Treg cells in shaping the immune system and the inflammatory responses. In this paper, we will discuss the role of these mechanisms in the control of immunity and autoimmunity and the mechanisms that underlie how these molecules control these responses.

Memory/effector (CD45RBlo) CD4 T cells are controlled directly by IL-10 and cause IL-22–dependent intestinal pathology

Interleukin-10 acts directly on CD45RBlo but not CD45RBhi cells to control colitis upon transfer into Rag1-deficient recipients.