HDAC Inhibitors as Epigenetic Regulators

The fall was especially precipitous in the BAL compartment, with only 3.4% of CD4+T cells expressing Foxp3 by day 11 (Fig. and retain Foxp3 expressionin vitro, suggesting that acute viral infection is capable of inducing a foreign-antigen-specific Treg response. The ability of influenza virus-induced regulatory T cells to suppress antigen-specific CD4+and CD8+T cell proliferation and cytokine production correlates closely to their ability to respond to influenza virus antigens, suggesting that virus-induced Tregs are capable of attenuating effector responses in an antigen-dependent manner. Collectively, these data demonstrate that primary acute viral infection is capable of inducing a robust, antigen-responsive, and suppressive regulatory T cell response. == INTRODUCTION == Immune responses to foreign antigens must Ridinilazole be carefully tempered in order to prevent inadvertent activation of self-reactive lymphocytes and to reduce collateral damage to normal tissue. A principal mechanism of immune moderation is mediated by regulatory T cells (Tregs), a distinct subset of T lymphocytes that contribute to immune system homeostasis and tolerance to self-antigens. A diverse assortment of Tregs have been described in both CD4+and CD8+T cell subsets, although Tregs expressing the CD4 coreceptor have been studied in greater detail and thus far have been ascribed greater physiological importance. In the CD4+Treg family, the transcription factor Foxp3 is a characteristic marker in mice and (to a lesser degree) humans, although Tregs not bearing this marker, such as Tr1 and Th3 Tregs, have been previously described (9,17). CD3+CD4+Foxp3+Tregs can be broadly divided into 2 subsets, with natural, or constitutive, Foxp3+Tregs (natural Tregs) being generated in the thymus through major histocompatibility class II (MHC-II)-dependent T cell receptor (TCR) interactions, resulting in high-avidity selection (19,21), while induced Foxp3+Tregs are generated in the periphery during an immune response and thus are likely to be potent regulators of ongoing inflammation (12,13). The ability of Tregs to recognize foreign antigens during influenza virus infection, and indeed during most encounters with microbial p12 pathogens, is unknown. Utilizing Tregs collected fromLeishmania major-infected animals and cultured with bone Ridinilazole marrow-derived dendritic cells (BMDCs) in the presence ofL. majormetacyclics, Suffia and coworkers (35) noted that the majority of CD25+Foxp3+CD4+Tregs in the draining lymph node during chronicL. majorinfection were antigen specific, providing early evidence that antigen specificity may be a crucial factor in the Treg-mediated suppression of foreign-antigen-specific immunity. Ertelt and colleagues, however, were unable to identify antigen-specific Treg priming with a murine model of acuteListeria monocytogenesinfection, suggesting that antigen-specific Treg responses are not engendered by every pathogen (14). The role of Tregs in acute infection is hypothesized to be driven by enhanced presentation of self-antigens, in which self-reactive natural Tregs limit effector responses in a bystander manner (3). Consistent with this, Liu and colleagues were able to identify only small Ridinilazole numbers (<1%) of MHC class II epitope-specific Tregs in Ridinilazole respiratory syncytial virus (RSV) infection (23). Similarly, very low numbers of influenza virus matrix 1-specific CD4+T cells demonstrating regulatory properties have also been identified in the peripheral blood mononuclear cells (PBMCs) of human donors (29). Influenza A virus infection is characterized by robust activation of both the innate and adaptive arms of immunity Ridinilazole and is associated with strong antigen-specific CD4+and cytotoxic CD8+T cell responses. Such lymphocyte activation, while important for the control of viral load, is also associated with considerable immunopathology leading to significant morbidity and death; thus, the induction of regulatory mechanisms may be vital (20). Recently studies identified a role for Foxp3+CD25+CD4+Tregs in murine models of RSV infection, further suggesting that Foxp3+Tregs may be influential in acute infection (16,22,32). The present study sought to examine the induction of Tregs in a murine model of nonlethal, primary influenza A virus infection and address the wider question of antigen specificity of Tregs in acute viral infection. Our findings demonstrate that influenza A virus induces a robust Foxp3+CD4+regulatory T cell response, particularly at early stages of infection, and that these cells are highly suppressiveex vivo. Influenza virus-induced Tregs proliferate in response to antigen, are widely disseminated, and stably express Foxp3. The ability of influenza virus-induced Tregs to suppress antigen-specific CD4+and CD8+T cell proliferation and cytokine production correlates with their antigen specificity, suggesting that such cells are capable of suppressing effector responses in an antigen-dependent manner. == MATERIALS AND METHODS == == Mice.