T-bet-dependent regulation of T cell responses during Trypanosoma cruzi infection

The human pathogen Trypanosoma cruzi is an intracellular parasite and the etiological agent of Chagas disease. Protective immune responses to T. cruzi are highly dependent on T helper 1 and CD8+ T cells which produce interferon-gamma. A deficiency in these responses has severe consequences on the ability to control infection. Our investigation into the role of the Th1 transcription factor, T-bet, during murine T. cruzi infection revealed that T-bet is required for resistance. Contrary to our expectations, T-bet was not required for the development of Th1 immunity during infection, as T-bet-deficient mice still developed interferon-gamma-producing T cells. However, T-bet was required to suppress the differentiation of Th17 cells and for the expansion of T. cruzi-specific CD8+ T cells. We first sought to determine the cause of reduced numbers of T. cruzi-specific CD8+ T cells in infected T-bet-deficient mice. First, we found that impaired migration or survival did not contribute to the low number of T. cruzi-specific CD8+ T cells. Secondly, we determined that reduced numbers of CD8+ T cells was not secondary to a defect in antigen-presenting cell activation or priming of CD8+ T cells. A recapitulation of defective expansion in mice with normal T-bet-expressing antigen-presenting cells demonstrated that T-bet expression in T cells was required. Thus, we determined that T-bet regulates the expansion of antigen-specific CD8+ T cells during T. cruzi infection in a T cell-intrinsic manner. Although it was evident T-bet had an integral role in suppressing the development of Th17 cells in response to infection with T. cruzi, several issues remained unclear. The first was the apparent lack of a negative regulatory effect of IFN-g/IFN-g-signaling on Th17 cells, which contradicted published reports. To clarify the role of IFN-g, we investigated the effect of IFN-g- or Stat-1-deficiency during T. cruzi infection. Surprisingly, IFN-g did not have a major role in up-regulating T-bet or for suppressing the development of Th17 responses, whereas Stat-1 was necessary for both. This was unexpected as Stat-1 is an IFN-g-inducible transcription factor, and its activation leads to T-bet induction. Thus, the T-bet-mediated inhibition of Th17 responses during T. cruzi infection is dependent on Stat-1, but not IFN-g. The final aim of this project was to identify the cytokines that negatively regulate Th17 differentiation in response to T. cruzi. We focused on the IL-12-family cytokines, IL-12 and IL-27, which are known to regulate T cell responses. Indeed, IL-12-deficient mice infected with T. cruzi developed a significant increase in Th17 cells similar to that observed in T-bet-deficient mice. Surprisingly, and in contrast to published results in other models, IL-27-deficient mice did not exhibit an increase in Th17 development. Our results demonstrate that IL-12, but not IL-27, is necessary for optimal T-bet expression and regulation of Th17 responses during T. cruzi infection

Cognitive Behavioral Therapy for Veterans Experiencing Insomnia: A Systematic Review

In this systematic literature review, research regarding veterans experiencing insomnia and the utilization of Cognitive Behavioral Therapy for Insomnia as an effective treatment modality were synthesized. Using the sociology research database SocINDEX; nine studies examining the effectiveness of Cognitive Behavioral Therapy as a treatment option for insomnia and insomnia related symptoms met criteria for the review. The Behavioral Model of Insomnia was used as the conceptual framework for this review. This framework was utilized to explore Cognitive Behavioral Therapy as an effective means of treating veterans experiencing insomnia. Studies included in this systematic review produced these findings: improvements in sleep quality, sleep efficiency, sleep onset latency, total sleep time, a reduction in depressive and insomnia symptoms, increased normalization of sleep, and a reduction in dysfunctional beliefs about sleep. This study contributes to the growing body of literature supporting Cognitive Behavioral Therapy for Insomnia as an evidenced based treatment option for veterans experiencing insomnia through a dissemination of the findings, strengths, limitations, and implications for future research

Cognitive Behavioral Therapy for Veterans Experiencing Insomnia: A Systematic Review

In this systematic literature review, research regarding veterans experiencing insomnia and the utilization of Cognitive Behavioral Therapy for Insomnia as an effective treatment modality were synthesized. Using the sociology research database SocINDEX; nine studies examining the effectiveness of Cognitive Behavioral Therapy as a treatment option for insomnia and insomnia related symptoms met criteria for the review. The Behavioral Model of Insomnia was used as the conceptual framework for this review. This framework was utilized to explore Cognitive Behavioral Therapy as an effective means of treating veterans experiencing insomnia. Studies included in this systematic review produced these findings: improvements in sleep quality, sleep efficiency, sleep onset latency, total sleep time, a reduction in depressive and insomnia symptoms, increased normalization of sleep, and a reduction in dysfunctional beliefs about sleep. This study contributes to the growing body of literature supporting Cognitive Behavioral Therapy for Insomnia as an evidenced based treatment option for veterans experiencing insomnia through a dissemination of the findings, strengths, limitations, and implications for future research

CpG and Interleukin-15 Synergize to Enhance IFN-γ Production by Activated CD8+ T Cells

Interleukin-15 (IL-15) regulates the development and maintenance of memory CD8+ T cells. Paradoxically, we previously reported that IL-15 could enhance CD8+ T-cell responses to IL-12, a proinflammatory cytokine required for optimal priming of effector CD8+ T cells. To expand the physiological relevance of these findings, we tested IL-15 for its ability to enhance T-cell responses to bacterial CpG. Expectedly, CpG enhanced the production of IFN-γ by CD8+ T cells polyclonally activated with anti-CD3. However, addition of IL-15 to CpG-stimulated cultures led to a striking increase in IFN-γ production. The effect of CpG and IL-15 was also evident with CD8+ T cells recovered from mice infected with the parasite Trypanosoma cruzi (T. cruzi) and restimulated with antigen. The observed synergy between CpG and IL-15 occurred in an IL-12-dependent manner, and this effect could even be demonstrated in cocultures of activated CD8+ T cells and CD4+CD25+ regulatory T cells. Although IFN-γ was not essential for CpG-induced IL-12, the ability of CpG and IL-15 to act on CD8+ T cells required expression of the IFN-γ-inducible transcription factor T-bet. These data have important implications for development of vaccines and design of therapies to boost CD8+ T-cell responses to infectious agents and tumors

CpG and Interleukin-15 Synergize to Enhance IFN- Production by Activated CD8+ T Cells

Interleukin-15 (IL-15) regulates the development and maintenance of memory CD8+ T cells. Paradoxically, we previously reported that IL-15 could enhance CD8+ T-cell responses to IL-12, a proinflammatory cytokine required for optimal priming of effector CD8+ T cells. To expand the physiological relevance of these findings, we tested IL-15 for its ability to enhance T-cell responses to bacterial CpG. Expectedly, CpG enhanced the production of IFN- by CD8+ T cells polyclonally activated with anti-CD3. However, addition of IL-15 to CpG-stimulated cultures led to a striking increase in IFN- production. The effect of CpG and IL-15 was also evident with CD8+ T cells recovered from mice infected with the parasite Trypanosoma cruzi (T. cruzi) and restimulated with antigen. The observed synergy between CpG and IL-15 occurred in an IL-12-dependent manner, and this effect could even be demonstrated in cocultures of activated CD8+ T cells and CD4+CD25+ regulatory T cells. Although IFN- was not essential for CpG-induced IL-12, the ability of CpG and IL-15 to act on CD8+ T cells required expression of the IFN--inducible transcription factor T-bet. These data have important implications for development of vaccines and design of therapies to boost CD8+ T-cell responses to infectious agents and tumors

CpG and Interleukin-15 Synergize to Enhance IFN-gamma Production by Activated CD8(+) T Cells

Interleukin-15 (IL-15) regulates the development and maintenance of memory CD8(+) T cells. Paradoxically, we previously reported that IL-15 could enhance CD8(+) T-cell responses to IL-12, a proinflammatory cytokine required for optimal priming of effector CD8(+) T cells. To expand the physiological relevance of these findings, we tested IL-15 for its ability to enhance T-cell responses to bacterial CpG. Expectedly, CpG enhanced the production of IFN-gamma by CD8(+) T cells polyclonally activated with anti-CD3. However, addition of IL-15 to CpG-stimulated cultures led to a striking increase in IFN-gamma production. The effect of CpG and IL-15 was also evident with CD8(+) T cells recovered from mice infected with the parasite Trypanosoma cruzi (T. cruzi) and restimulated with antigen. The observed synergy between CpG and IL-15 occurred in an IL-12-dependent manner, and this effect could even be demonstrated in cocultures of activated CD8(+) T cells and CD4(+)CD25(+) regulatory T cells. Although IFN-gamma was not essential for CpG-induced IL-12, the ability of CpG and IL-15 to act on CD8(+) T cells required expression of the IFN-gamma-inducible transcription factor T-bet. These data have important implications for development of vaccines and design of therapies to boost CD8(+) T-cell responses to infectious agents and tumors

MHCII glycosylation modulates Bacteroides fragilis carbohydrate antigen presentation

N-linked glycans on class II MHC molecules are required for the presentation of glycoantigens, but not peptide antigens

Blimp-1–mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis

CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported inToxoplasma encephalitis (TE)–susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell–intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches

Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells

The immune synapse is an exquisitely evolved means of communication between T cells and antigen-presenting cells (APCs) during antigen recognition. Recent evidence points to the transfer of RNA via exosomes as a novel mode of intercellular communication. Here we show that exosomes of T, B and dendritic immune cells contain microRNA (miRNA) repertoires that differ from those of their parent cells. We investigate whether miRNAs are exchanged during cognate immune interactions, and demonstrate the existence of antigen-driven unidirectional transfer of miRNAs from the T cell to the APC, mediated by the delivery of CD63+ exosomes on immune synapse formation. Inhibition of exosome production by targeting neutral sphingomyelinase-2 impairs transfer of miRNAs to APCs. Moreover, miRNAs transferred during immune synapsis are able to modulate gene expression in recipient cells. Thus, our results support a mechanism of cellular communication involving antigen-dependent, unidirectional intercellular transfer of miRNAs by exosomes during immune synapsis

CD40 signaling to the rescue: A CD8 exhaustion perspective in chronic infectious diseases

Chronic infectious diseases such as HIV, HBV, and HCV, among others, cause severe morbidity and mortality globally. Progressive decline in CD8 functionality, survival, and proliferative potential—a phenomenon referred to as CD8 exhaustion—is believed to be responsible for poor pathogen control in chronic infectious diseases. While the role of negative inhibitory receptors such as PD-1 in augmenting CD8 exhaustion has been extensively studied, the role of positive costimulatory receptors remains poorly understood. In this review, we discuss how one such costimulatory pathway, CD40–CD40L, regulates CD8 dysfunction and rescue. While the significance of this pathway has been extensively investigated in models of autoimmunity, acute infectious diseases, and tumor models, the role played by CD40–CD40L in regulating CD8 exhaustion in chronic infectious diseases is just beginning to be understood. Considering that monotherapy with blocking antibodies targeting inhibitory PD-1-PD-L1 pathway is only partially effective at ameliorating CD8 exhaustion and that humanized CD40 agonist antibodies are currently available, a better understanding of the role of the CD40–CD40L pathway in chronic infectious diseases will pave the way for the development of more robust immunotherapeutic and prophylactic vaccination strategies