In organisms from insects to vertebrates, Toll-like receptors (TLRs) are primary pathogen detectors that activate downstream pathways, specifically those that direct expression of innate immune effector genes. TLRs also have roles in development in many species. The sea anemone is a useful cnidarian model to study the origins of TLR signaling because its genome encodes a single TLR and homologs of many downstream signaling components, including the NF-κB pathway. We have characterized the single TLR (Nv-TLR) and demonstrated that it can activate canonical NF-κB signaling in human cells. Furthermore, we show that the intracellular Toll/IL-1 receptor (TIR) domain of Nv-TLR can interact with the human TLR adapter proteins MAL and MYD88. We demonstrate that the coral pathogen causes a rapidly lethal disease in and that heat-inactivated and bacterial flagellin can activate a reconstituted Nv-TLR-to-NF-κB pathway in human cells. By immunostaining of anemones, we show that Nv-TLR is expressed in a subset of cnidocytes and that many of these Nv-TLR-expressing cells also express Nv-NF-κB. Additionally, the nematosome, which is a-specific multicellular structure, expresses Nv-TLR and many innate immune pathway homologs and can engulf Morpholino knockdown indicates that Nv-TLR also has an essential role during early embryonic development. Our characterization of this primitive TLR and identification of a bacterial pathogen for reveal ancient TLR functions and provide a model for studying the molecular basis of cnidarian disease and immunity.
Immunosuppression increases the risk of cancers associated with viral infection 1. In particular, squamous cell carcinoma (SCC) of the skin has a >100-fold increased risk in immunosuppressed patients and has been associated with beta human papillomavirus (β-HPV) infection 2-4. Previous studies, however, have failed to establish a causative role for HPVs in driving skin cancer development. Herein, we provide an alternative explanation for this association by demonstrating that the T cell immunity against commensal papillomaviruses suppresses skin cancer in immunocompetent hosts. The loss of this immunity, rather than the oncogenic effect of HPVs, is the reason for the markedly increased risk of skin cancer in immunosuppressed patients. To investigate the impact of papillomavirus on carcinogen-driven skin cancer, we colonized several Reprint and permissions information is available at www.nature.com/reprints.Users may view, print, copy, and download text and datamine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://
With the Food and Drug Administration and other worldwide regulatory authorities' approval of ipilimumab (Yervoy), sipuleucel-T (Provenge), nivolumab (Opdivo), and pembrolizumab (Keytruda), oncologic therapy has now moved into noncancer cell targets within the immune system. For many nonimmunologists, understanding how these vastly different therapies work to improve survival, like no other therapies have in the past, is a challenge. The present report reviews the normal function of the immune system, how cancers escape the normal immune system, and how these new therapies improve immune system reactions against cancers. The Oncologist 2016;21:233-243 Implications for Practice: Oncologists have tremendous experience with therapies that target the cancer cells. New biologic agents have been rapidly introduced recently that target not cancer cells, but the patient's immune cells. The mechanisms of action of these immune-based biologic agents are within the host immune system.To understand these new biologic therapies, basic knowledge of normal and abnormal immune function is essential. The present report explains the up-to-date basic immune normal and abnormal function and prepares the oncologist to understand how the new drugs work, why they work, and why there are associated adverse events.
Since the sequencing of the human genome during the 1990s, steady progress in understanding genetic alterations and gene product functions are being unraveled. In cancer, this is proceeding very fast and demonstrates that genetic mutations occur very rapidly to allow for selection of survival traits within various cancer clones. Hundreds of mutations have been identified in single individual cancers, but spread across many clones in the patient's body. Precision oncology will require accurate measurement of these cancer survival-benefiting mutations to develop strategies for effective therapy. Inhibiting these cellular mechanisms is a first step, but these malignant cells need to be eliminated by the host's mechanisms, which we are learning to direct more specifically. Cancer is one of the most complicated cellular aberrations humans have encountered. Rapidly developing significant survival traits require prompt, repeated, and total body measurements of these attributes to effectively develop multi-agent treatment of the individual's malignancy. Focused drug development to inhibit these beneficial mutations is critical to slowing cancer cell growth and, perhaps, triggering apoptosis. In many cases, activation and targeting of the immune system to kill the remaining malignant cells is essential to a cure.
Melanoma and melanocytic nevi harbor shared lineage-specific antigens and oncogenic mutations. Yet, the relationship between the immune system and melanocytic nevi is unclear. Using a patient-derived xenograft (PDX) model, we found that 81.8% of the transplanted nevi underwent spontaneous regression, while peripheral skin remained intact. Nevus-resident CD4+ T helper 1 cells, which exhibited a massive clonal expansion to melanocyte-specific antigens, were responsible for nevus rejection. Boosting regulatory T cell suppressive function with low-dose exogenous human interleukin-2 injection or treatment with a human leukocyte antigen (HLA) class II–blocking antibody prevented nevus rejection. Notably, mice with rejected nevus PDXs were protected from melanoma tumor growth. We detected a parallel CD4+ T cell–dominant immunity in clinically regressing melanocytic nevi. These findings reveal a mechanistic explanation for spontaneous nevus regression in humans and posit the activation of nevus-resident CD4+ effector T cells as a novel strategy for melanoma immunoprevention and treatment.
The innate immune system is the most primitive branch of the immune system and is responsible for recognizing pathogens and eliciting responses such as inflammation and antimicrobial peptide production in many organisms. Toll‐like receptors (TLRs) are transmembrane receptors that have been characterized in organisms from insects to humans. TLRs detect molecules expressed by microbial pathogens, and then activate the NF‐κB transcription factor signaling pathway to turn on the expression of innate immune effector genes. Recent genome and transcriptome sequencing efforts have led to the identification of TLR‐like genes in organisms more basal to insects, but the biological roles of these basal TLRs are not well understood. In this project, we are characterizing a TLR‐like protein in the sea anemone Nematostella vectensis (Nv), a model organism for the phylum Cnidaria. The single Nv‐TLR harbors leucine‐rich extracellular, transmembrane, and intracellular TIR domains, consistent with TLR structures in higher organisms, including humans. In cell culture‐based reporter assays, we show that Nv‐TLR can activate the human NF‐κB signaling pathway and this pathway activation can be stimulated by the biologically relevant bacterium Vibrio coralliilyticus and purified flagellin from Salmonella typhimurium. In biochemical studies, the intracellular TIR domain of Nv‐TLR can bind to human NF‐κB signal transduction adapter proteins MAL and MyD88, and the extracellular domain of Nv‐TLR can directly bind to flagellin. In anemones, Nv‐TLR and Nv‐NF‐κB (and most intermediate TLR to NF‐κB signaling proteins) are expressed in cnidocytes, both in the body column and in a Nematostella‐specific circulating organ called the nematosome. Nv‐TLR is also required for embryonic development in N. vectensis. Ongoing studies are characterizing the biochemical aspects of the flagellin‐TLR interaction. Taken together, these studies suggest that a TLR‐to‐NF‐κB pathway is functionally conserved from cnidarians to humans. Moreover, these studies provide insight into the evolutionary basis of vertebrate innate immunity, and shed light on how simple organisms respond at the molecular level to environmental and biological stressors.Support or Funding InformationUndergraduate Research Opportunities Program (Boston University), National Science Foundation, Arnold and Mabel Beckman FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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