Effector CD8+ T cells are typically thought to be a homogenous group of cytotoxic cells that produce interferon-(IFN) γ. However, recent findings have challenged this notion because multiple subsets ...of CD8+ T cells have been described, each with distinct effector functions and cytotoxic potential. These subsets, referred to as the Tc subsets, have also been detected in tumor microenvironments (TMEs), where they potentially influence the antitumor response and patient outcomes. In this review, we highlight the prevalence and roles of Tc subsets in the TME. We also discuss their therapeutic applications in the context of adoptive immunotherapy to treat cancer.
There are multiple subsets of CD8+ T cells, not all of which have cytotoxic function and produce IFN-γ.A variety of Tc subsets have been detected within the TME and, depending on the subset, can be either positively or negatively correlated with prognosis.In the context of adoptive immunotherapy to treat cancer, the degree of tumor control is greatly influenced by the subset of T cells transferred.
The paracaspase MALT1 plays an important role in immune receptor-driven signaling pathways leading to NF-κB activation. MALT1 promotes signaling by acting as a scaffold, recruiting downstream ...signaling proteins, as well as by proteolytic cleavage of multiple substrates. However, the relative contributions of these two different activities to T and B cell function are not well understood. To investigate how MALT1 proteolytic activity contributes to overall immune cell regulation, we generated MALT1 protease-deficient mice (Malt1(PD/PD)) and compared their phenotype with that of MALT1 knockout animals (Malt1(-/-)). Malt1(PD/PD) mice displayed defects in multiple cell types including marginal zone B cells, B1 B cells, IL-10-producing B cells, regulatory T cells, and mature T and B cells. In general, immune defects were more pronounced in Malt1(-/-) animals. Both mouse lines showed abrogated B cell responses upon immunization with T-dependent and T-independent Ags. In vitro, inactivation of MALT1 protease activity caused reduced stimulation-induced T cell proliferation, impaired IL-2 and TNF-α production, as well as defective Th17 differentiation. Consequently, Malt1(PD/PD) mice were protected in a Th17-dependent experimental autoimmune encephalomyelitis model. Surprisingly, Malt1(PD/PD) animals developed a multiorgan inflammatory pathology, characterized by Th1 and Th2/0 responses and enhanced IgG1 and IgE levels, which was delayed by wild-type regulatory T cell reconstitution. We therefore propose that the pathology characterizing Malt1(PD/PD) animals arises from an immune imbalance featuring pathogenic Th1- and Th2/0-skewed effector responses and reduced immunosuppressive compartments. These data uncover a previously unappreciated key function of MALT1 protease activity in immune homeostasis and underline its relevance in human health and disease.
Equine glandular gastric disease (EGGD) is a common disease among athletic horses that can negatively impact health and performance. The pathophysiology of this EGGD remains poorly understood. ...Previous studies using controlled populations of horses identified differences in the gastric glandular mucosal microbiome associated with disease. The objective of this study was to compare the gastric microbiome in horses with EGGD and those without across multiple barns and differing management practices. We hypothesized that alterations in the microbiome of the gastric glandular mucosa are associated with EGGD. A secondary objective was to perform a risk factor analysis for EGGD using the diet and management data collected. Microbial populations of biopsies from normal pyloric mucosa of horses without EGGD (control biopsies), normal pyloric mucosa of horses with EGGD (normal biopsies) and areas of glandular mucosal disruption in horses with EGGD (lesion biopsies) were compared. Lesion biopsies had a different microbial community structure than control biopsies. Control biopsies had a higher read count for the phylum Actinomycetota compared to lesion biopsies. Control biopsies also had an enrichment of the genera Staphylococcus and Lawsonella and the species Streptococcus salivarius. Lesion biopsies had an enrichment of the genera Lactobacillus and Actinobacillus and the species Lactobacillus equigenerosi. These results demonstrate differences in the gastric glandular microbiome between sites of disrupted mucosa in horses with EGGD compared to pyloric mucosa of horses without EGGD. Risk factor analysis indicated that exercise duration per week was a risk factor for EGGD.
Thrombocytes are the avian equivalent to mammalian platelets. In addition to their hemostatic effects, mammalian platelets rely in part on pattern recognition receptors, such as the Toll-like ...receptors (TLR), to detect the presence of pathogens and signal the release of certain cytokines. Ligands for TLRs include lipopolysaccharide (LPS), which is bound by TLR4, as well as unmethylated CpG DNA motifs, which are bound by TLR9 in mammals and TLR21 in chickens. Similar to mammalian platelets, avian thrombocytes have been shown to express TLR4 and secrete some pro-inflammatory cytokines in response to LPS treatment. However, the full extent of the contributions made by thrombocytes to host immunity has yet to be elucidated. Importantly, the mechanisms by which TLR stimulation may modulate thrombocyte effector functions have not been well characterized. As such, the objective of the present study was to gain further insight into the immunological role of thrombocytes by analyzing their responses to treatment with ligands for TLR4 and TLR21. To this end, we quantified the relative expression of several immune system genes at 1, 3, 8 and 18 hours post-treatment using real-time RT-PCR. Furthermore, production of nitric oxide and phagocytic activity of thrombocytes was measured after their activation with TLR ligands. We found that thrombocytes constitutively express transcripts for both pro- and anti-inflammatory cytokines, in addition to those associated with anti-viral responses and antigen presentation. Moreover, we found that both LPS and CpG oligodeoxynucleotides (ODN) induced robust pro-inflammatory responses in thrombocytes, as characterized by more than 100 fold increase in interleukin (IL)-1β, IL-6 and IL-8 transcripts, while only LPS enhanced nitric oxide production and phagocytic capabilities. Future studies may be aimed at examining the responses of thrombocytes to other TLR ligands.
The ability to mount a strong immune response against pathogens is crucial for mammalian survival. However, excessive and uncontrolled immune reactions can lead to autoimmunity. Unraveling how the ...reactive versus tolerogenic state is controlled might point toward novel therapeutic strategies to treat autoimmune diseases. The surface receptor Toso/Faim3 has been linked to apoptosis, IgM binding, and innate immune responses. In this study, we used Toso-deficient mice to investigate the importance of Toso in tolerance and autoimmunity. We found that Toso ⁻/⁻ mice do not develop severe experimental autoimmune encephalomyelitis (EAE), a mouse model for the human disease multiple sclerosis. Toso ⁻/⁻ dendritic cells were less sensitive to Toll-like receptor stimulation and induced significantly lower levels of disease-associated inflammatory T-cell responses. Consistent with this observation, the transfer of Toso ⁻/⁻ dendritic cells did not induce autoimmune diabetes, indicating their tolerogenic potential. In Toso ⁻/⁻ mice subjected to EAE induction, we found increased numbers of regulatory T cells and decreased encephalitogenic cellular infiltrates in the brain. Finally, inhibition of Toso activity in vivo at either an early or late stage of EAE induction prevented further disease progression. Taken together, our data identify Toso as a unique regulator of inflammatory autoimmune responses and an attractive target for therapeutic intervention.
Highlights ► Treatment of chickens with TLR ligands reduced shedding of avian influenza virus. ► Treatment with poly I:C resulted in a 5 log decrease in virus shedding. ► CpG treatment reduced virus ...shedding by more than 3 log. ► LPS treatment also reduced virus shedding by ∼2 log. ► Immunity correlated with IFN-γ, IFN-α and IL-8 expression.
Immunotherapies targeting PD-1/PD-L1 are now widely used in the clinic to treat a variety of malignancies. While most of the research on T cell exhaustion and PD-1 blockade has been focused on ...conventional αβ T cells, the contribution of innate-like T cells such as γδ T cells to anti-PD-1/PD-L1 mediated therapy is limited. Here we show that tumor reactive γδ T cells respond to PD-1 blockade in a Merkel cell carcinoma (MCC) patient experiencing a complete response to therapy. We find clonally expanded γδ T cells in the blood and tumor after pembrolizumab treatment, and this Vγ2Vδ1 clonotype recognizes Merkel cancer cells in a TCR-dependent manner. Notably, the intra-tumoral γδ T cells in the MCC patient are characterized by higher expression of PD-1 and TIGIT, relative to conventional CD4 and CD8 T cells. Our results demonstrate that innate-like T cells could also contribute to an anti-tumor response after PD-1 blockade.
...of the top papers assigned to each challenge, those assessing ocean health received the highest annual mean number of citations, followed by papers on understanding relationships between human ...pressures and ecosystems, and those dealing with understanding the role of biodiversity in maintaining ecosystems functionality (Table 1). To date, restoration efforts have focused on coastal ecosystems, but with increasing exploration for hydrocarbons and other resources offshore and in areas beyond national jurisdiction, approaches for deep-sea and open sea restoration should be explored and tested; (N4) Moving from descriptive studies to those providing functional assessments, improving the understanding of marine ecosystems, supporting management and sustainability strategies for human activities in the ocean, in line with the UN DOSSD; (N5) Understanding the cause-effect pathways and the response of ecosystems to increasing cumulative human impacts and climate change (Ortiz et al., 2018), as drivers of shifts in most marine ecosystems, altering species distributions and threatening biodiversity (Halpern et al., 2019). ...this challenge is complex and requires novel methods of assessment and models spanning across disciplines (Crain et al., 2008; Phillips et al., 2019). Important knowledge gaps restrict our understanding of traits that facilitate invasions and the magnitude of their impacts, our capacity to predict future shifts in ecosystem processes and functioning due to invasive species, and our ability to propose adequate mitigation measures; (S3) Assessing urban development and subsequent loss of natural coastlines and ecosystem services (Barragán and de Andrés, 2015) (S4) Understanding the impacts of human activities as well as climate change in the deep ocean (Levin and Le Bris, 2015; Danovaro et al., 2017) (S5) Considering the land-ocean continuum, with major terrestrial and riverine inputs to the ocean (Xenopoulos et al., 2017).
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