Post-Transcriptional and Translational Mechanisms of Regulation of Gene Expression in T Cell Subsets

The immune system is under strict regulatory control to ensure homeostasis of inflammatory responses, lying dormant when not needed but quick to act when called upon. Small changes in gene expression can lead to drastic changes in lineage commitment, cellular function, and immunity. Conventional assessment of these changes centered on the analysis of mRNA levels through a variety of methodologies, including microarrays. However, mRNA synthesis does not always correlate directly to protein synthesis and downstream functional activity. Work conducted in recent years has begun to shed light on the various post-transcriptional changes that occur in response to a dynamic external environment in which a given immune cell type encounters. In this chapter, we provide a critical review of key post-transcriptional and translational mechanisms of regulation of gene expression in the immune system, with an emphasis of these regulatory processes in various CD4+ T cell subsets and their related effector functions

Functional crosstalk between dendritic cells and Foxp3+ regulatory T cells in the maintenance of immune tolerance

Peripheral immune tolerance requires a controlled balance between the maintenance of self-tolerance and the capacity to engage protective immune responses against pathogens. Dendritic cells (DCs) serve as sentinels of the immune system by sensing environmental and inflammatory signals, and play an essential role in the maintenance of immune tolerance. To achieve this, DC play a key role in dictating the outcome of immune responses by influencing the balance between inflammatory or Foxp3+ regulatory T (Treg) cell responses. At the heart of this immunological balance is a finely regulated DC and Treg cell crosstalk whereby Treg cells modulate DC phenotype and function, and DC drive the differentiation of Foxp3+ Treg cells in order to control immune responses. This review will focus on recent advances, which highlight the importance of this bidirectional DC and Treg cell crosstalk during the induction of tolerance and organ-specific autoimmunity. More specifically, we will discuss how Treg cells modulate DC function for the suppression of inflammatory responses and how DC subsets employ diverse mechanisms to drive differentiation of Treg cells. Finally, we will discuss the therapeutic potential of tolerogenic DCs for the induction of tolerance in autoimmune diseases

Plasmodium chabaudi AS Infection Induces CD4+ Th1 Cells and Foxp3+T-bet+ Regulatory T Cells That Express CXCR3 and Migrate to CXCR3 Ligands

Control and elimination of blood-stage Plasmodium chabaudi AS infection requires CD4+ Th1 cells that secrete IFN-γ and T follicular help (Tfh) cells together with B cell production of antibody. Foxp3+ regulatory T cells (Tregs) are also crucial to protect the host from immunopathology and severe disease, but these cells can suppress protective immune responses to malaria. The chemokine receptor CXCR3 expressed by activated T cells is important for trafficking of CD4+ Th1 cells to sites of inflammation and infection. Previous studies demonstrated CXCR3 is expressed on CD4+ T cells in the spleen during malaria, but the phenotype was not defined. We identified the phenotype of CD4+ T cells that expressed CXCR3 in C57BL/6 (B6) mice during acute P. chabaudi AS infection by analyzing expression of the transcription factors T-bet and Foxp3. We also investigated if CXCR3 contributes to control of parasite replication and survival. The frequency and number of CD4+CXCR3+ T cells increased dramatically in the spleen of infected B6 mice coincident with increased CD4+IFN-γ+ T cells. CXCR3 was up-regulated on effector CD4+Foxp3− T cells as well as Foxp3+ Tregs. Consistent with our previous observations, CD4+T-bet+Foxp3− T cells increased in B6 mice during acute infection. T-bet+Foxp3+ Tregs also increased significantly and a high frequency of these cells expressed CXCR3 supporting the notion that these cells may be Th1-like Tregs. Despite this, the percentage of CD4+Foxp3+ Tregs from infected B6 mice that migrated in vitro to the CXCR3 ligands CXCL9 and CXCL10 was significantly less than naïve mice. To investigate the in vivo contribution of CXCR3 to control of acute blood-stage malaria, we compared the course and outcome of P. chabaudi AS infection in wild-type (WT) B6 and CXCR3-deficient mice. Parasitemia levels were significantly higher around the time of peak parasitemia in CXCR3−/− compared to WT mice but survival was similar suggesting a role for CXCR3 in controlling parasite replication during acute P. chabaudi AS infection. Together, our findings indicate Th1-like CD4+T-bet+Foxp3+ Tregs that express CXCR3 are induced during acute blood-stage malaria and suggest CXCR3 expression on CD4+ Th1 cells may contribute to their migration to the spleen

Pleiotropic Effects of IL-33 on CD4+ T Cell Differentiation and Effector Functions

IL-33, a member of the IL-1 family of cytokines, was originally described in 2005 as a promoter of type 2 immune responses. However, recent evidence reveals a more complex picture. This cytokine is released locally as an alarmin upon cellular damage where innate cell types respond to IL-33 by modulating their differentiation and influencing the polarizing signals they provide to T cells at the time of antigen presentation. Moreover, the prominent expression of the IL-33 receptor, ST2, on GATA3+ T helper 2 cells (TH2) demonstrated that IL-33 could have a direct impact on T cells. Recent observations reveal that T-bet+ TH1 cells and Foxp3+ regulatory T (TREG) cells can also express the ST2 receptor, either transiently or permanently. As such, IL-33 can have a direct effect on the dynamics of T cell populations. As IL-33 release was shown to play both an inflammatory and a suppressive role, understanding the complex effect of this cytokine on T cell homeostasis is paramount. In this review, we will focus on the factors that modulate ST2 expression on T cells, the effect of IL-33 on helper T cell responses and the role of IL-33 on TREG cell function

IL-2 as a therapeutic target for the restoration of Foxp3+ regulatory T cell function in organ-specific autoimmunity: implications in pathophysiology and translation to human disease

Peripheral immune tolerance requires a finely controlled balance between tolerance to self-antigens and protective immunity against enteric and invading pathogens. Self-reactive T cells sometimes escape thymic clonal deletion, and can subsequently provoke autoimmune diseases such as type 1 diabetes (T1D) unless they are controlled by a network of tolerance mechanisms in the periphery, including CD4+ regulatory T cells (Treg) cells. CD4+ Treg cells are characterized by the constitutive expression of the IL-2Rα chain (CD25) and preferentially express the forkhead winged helix transcriptional regulator Foxp3. These cells have been shown to possess immunosuppressive properties towards various immune cell subsets and their defects are thought to contribute to many autoimmune disorders. Strong evidence shows that IL-2 is one of the important stimulatory signals for the development, function and fitness of Treg cells. The non-obese diabetic (NOD) mouse model, a prototypic model of spontaneous autoimmunity, mimics many features of human T1 D. Using this model, the contribution of the IL-2-IL-2R pathway to the development of T1 D and other autoimmune disorders has been extensively studied. In the past years, strong genetic and molecular evidence has indicated an essential role for the IL-2/IL-2R pathway in autoimmune disorders. Thus, the major role of IL-2 is to maintain immune tolerance by promoting Treg cell development, functional fitness and stability. Here we first summarize the genetic and experimental evidence demonstrating a role for IL-2 in autoimmunity, mainly through the study of the NOD mouse model, and analyze the cellular and molecular mechanisms of its action on Treg cells. We then move on to describe how this data can be translated to applications for human autoimmune diseases by using IL-2 as a therapeutic agent to restore Treg cell fitness, numbers and functions

Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens

Natural regulatory T (T reg) cells are involved in control of the immune response, including response to pathogens. Previous work has demonstrated that the repertoire of natural T reg cells may be biased toward self-antigen recognition. Whether they also recognize foreign antigens and how this recognition contributes to their function remain unknown. Our studies addressed the antigenic specificity of natural T reg cells that accumulate at sites of chronic infection with Leishmania major in mice. Our results support the idea that natural T reg cells are able to respond specifically to foreign antigens in that they strongly proliferate in response to Leishmania-infected dendritic cells, they maintain Foxp3 expression, and Leishmania-specific T reg cell lines can be generated from infected mice. Surprisingly, the majority of natural T reg cells at the infected site are Leishmania specific. Further, we showed that parasite-specific natural T reg cells are restricted to sites of infection and that their survival is strictly dependent on parasite persistence

CD4+CD25+ Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor β1 Production and Responsiveness

CD4+CD25+ regulatory T cells inhibit organ-specific autoimmune diseases induced by CD4+CD25−T cells and are potent suppressors of T cell activation in vitro. Their mechanism of suppression remains unknown, but most in vitro studies suggest that it is cell contact–dependent and cytokine independent. The role of TGF-β1 in CD4+CD25+ suppressor function remains unclear. While most studies have failed to reverse suppression with anti–transforming growth factor (TGF)-β1 in vitro, one recent study has reported that CD4+CD25+ T cells express cell surface TGF-β1 and that suppression can be completely abrogated by high concentrations of anti–TGF-β suggesting that cell-associated TGF-β1 was the primary effector of CD4+CD25+-mediated suppression. Here, we have reevaluated the role of TGF-β1 in CD4+CD25+-mediated suppression. Neutralization of TGF-β1 with either monoclonal antibody (mAb) or soluble TGF-βRII-Fc did not reverse in vitro suppression mediated by resting or activated CD4+CD25+ T cells. Responder T cells from Smad3−/− or dominant-negative TGF-β type RII transgenic (DNRIITg) mice, that are both unresponsive to TGF-β1–induced growth arrest, were as susceptible to CD4+CD25+-mediated suppression as T cells from wild-type mice. Furthermore, CD4+CD25+ T cells from neonatal TGF-β1−/− mice were as suppressive as CD4+CD25+ from TGF-β1+/+ mice. Collectively, these results demonstrate that CD4+CD25+ suppressor function can occur independently of TGF-β1