STING activation promotes autologous type I interferon-dependent development of type 1 regulatory T cells during malaria.

The development of highly effective malaria vaccines and improvement of drug-treatment protocols to boost antiparasitic immunity are critical for malaria elimination. However, the rapid establishment of parasite-specific immune regulatory networks following exposure to malaria parasites hampers these efforts. Here, we identified stimulator of interferon genes (STING) as a critical mediator of type I interferon production by CD4+ T cells during blood-stage Plasmodium falciparum infection.

IL-10-producing Th1 cells possess a distinct molecular signature in malaria.

Control of intracellular parasites responsible for malaria requires host IFN-γ+T-bet+CD4+ T cells (Th1 cells) with IL-10 produced by Th1 cells to mitigate the pathology induced by this inflammatory response. However, these IL-10-producing Th1 (induced type I regulatory [Tr1]) cells can also promote parasite persistence or impair immunity to reinfection or vaccination. Here, we identified molecular and phenotypic signatures that distinguished IL-10-Th1 cells from IL-10+Tr1 cells in Plasmodium falciparum-infected people who participated in controlled human malaria infection studies, as well as C57BL/6 mice with experimental malaria caused by P.

The NK cell granule protein NKG7 regulates cytotoxic granule exocytosis and inflammation.

Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases.

Type I Interferons Suppress Anti-parasitic Immunity and Can Be Targeted to Improve Treatment of Visceral Leishmaniasis.

Type I interferons (IFNs) play critical roles in anti-viral and anti-tumor immunity. However, they also suppress protective immune responses in some infectious diseases. Here, we identify type I IFNs as major upstream regulators of CD4 T cells from visceral leishmaniasis (VL) patients.

Distinct Roles for CD4 Foxp3 Regulatory T Cells and IL-10-Mediated Immunoregulatory Mechanisms during Experimental Visceral Leishmaniasis Caused by .

The outcome of intracellular parasitic infection can be determined by the immunoregulatory activities of natural regulatory CD4 Foxp3 T (Treg) cells and the anti-inflammatory cytokine IL-10. These mechanisms protect tissue but can also suppress antiparasitic CD4 T cell responses. The specific contribution of these regulatory pathways during human parasitic diseases remains unclear.

Rapid loss of group 1 innate lymphoid cells during blood stage infection.

Objectives: Innate lymphoid cells (ILCs) share many characteristics with CD4 T cells, and group 1 ILCs share a requirement for T-bet and the ability to produce IFNγ with T helper 1 (Th1) cells. Given this similarity, and the importance of Th1 cells for protection against intracellular protozoan parasites, we aimed to characterise the role of group 1 ILCs during infection.

Methods: We quantified group 1 ILCs in peripheral blood collected from subjects infected with with 3D7 as part of a controlled human malaria infection study, and in the liver and spleens of AS-infected mice.

Galectin-1 Impairs the Generation of Anti-Parasitic Th1 Cell Responses in the Liver during Experimental Visceral Leishmaniasis.

Many infectious diseases are characterized by the development of immunoregulatory pathways that contribute to pathogen persistence and associated disease symptoms. In diseases caused by intracellular parasites, such as visceral leishmaniasis (VL), various immune modulators have the capacity to negatively impact protective CD4 T cell functions. Galectin-1 is widely expressed on immune cells and has previously been shown to suppress inflammatory responses and promote the development of CD4 T cells with immunoregulatory characteristics.

Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria.

Differentiation of naïve CD4 T cells into functionally distinct T helper subsets is crucial for the orchestration of immune responses. Due to extensive heterogeneity and multiple overlapping transcriptional programs in differentiating T cell populations, this process has remained a challenge for systematic dissection . By using single-cell transcriptomics and computational analysis using a temporal mixtures of Gaussian processes model, termed GPfates, we reconstructed the developmental trajectories of Th1 and Tfh cells during blood-stage infection in mice.

Combined Immune Therapy for the Treatment of Visceral Leishmaniasis.

Chronic disease caused by infections, cancer or autoimmunity can result in profound immune suppression. Immunoregulatory networks are established to prevent tissue damage caused by inflammation. Although these immune checkpoints preserve tissue function, they allow pathogens and tumors to persist, and even expand.

Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology.

Tumor necrosis factor (TNF) is critical for controlling many intracellular infections, but can also contribute to inflammation. It can promote the destruction of important cell populations and trigger dramatic tissue remodeling following establishment of chronic disease. Therefore, a better understanding of TNF regulation is needed to allow pathogen control without causing or exacerbating disease.

IL-17A-Producing γδ T Cells Suppress Early Control of Parasite Growth by Monocytes in the Liver.

Intracellular infections, such as those caused by the protozoan parasite Leishmania donovani, a causative agent of visceral leishmaniasis (VL), require a potent host proinflammatory response for control. IL-17 has emerged as an important proinflammatory cytokine required for limiting growth of both extracellular and intracellular pathogens. However, there are conflicting reports on the exact roles for IL-17 during parasitic infections and limited knowledge about cellular sources and the immune pathways it modulates.

The Regulation of CD4(+) T Cell Responses during Protozoan Infections.

CD4(+) T cells are critical for defense against protozoan parasites. Intracellular protozoan parasite infections generally require the development of a Th1 cell response, characterized by the production of IFNγ and TNF that are critical for the generation of microbicidal molecules by phagocytes, as well as the expression of cytokines and cell surface molecules needed to generate cytolytic CD8(+) T cells that can recognize and kill infected host cells. Over the past 25 years, much has been learnt about the molecular and cellular components necessary for the generation of Th1 cell responses, and it has become clear that these responses need to be tightly controlled to prevent disease.

Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity.

Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cellular immune responses through activation of type I IFN signaling. Recent evidence suggests that immune suppression and susceptibility to the malaria parasite, Plasmodium, is mediated by type I IFN; however, it is unclear how type I IFN suppresses immunity to blood-stage Plasmodium parasites. During experimental severe malaria, CD4+ Th cell responses are suppressed, and conventional DC (cDC) function is curtailed through unknown mechanisms.

Tissue requirements for establishing long-term CD4+ T cell-mediated immunity following Leishmania donovani infection.

Organ-specific immunity is a feature of many infectious diseases, including visceral leishmaniasis caused by Leishmania donovani. Experimental visceral leishmaniasis in genetically susceptible mice is characterized by an acute, resolving infection in the liver and chronic infection in the spleen. CD4+ T cell responses are critical for the establishment and maintenance of hepatic immunity in this disease model, but their role in chronically infected spleens remains unclear.

Critical roles for LIGHT and its receptors in generating T cell-mediated immunity during Leishmania donovani infection.

LIGHT (TNFSF14) is a member of the TNF superfamily involved in inflammation and defence against infection. LIGHT signals via two cell-bound receptors; herpes virus entry mediator (HVEM) and lymphotoxin-beta receptor (LTβR). We found that LIGHT is critical for control of hepatic parasite growth in mice with visceral leishmaniasis (VL) caused by infection with the protozoan parasite Leishmania donovani.