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De Yang, M.D., Ph.D.
The immune system relies on the highly orchestrated action of many cellular and humoral components to maintain homeostasis and to fend off immunologic non-self intruders. An intact layer of epithelium and skin acts as a mechanical barrier to separate the inner environment of an individual from the outside environment. When this barrier is breached due to injury or infection non-self substances, including microorganisms, enter the host and immediately trigger innate immune responses, including generation and/or mobilization of humoral mediators (e.g., cytokines, chemotactic factors, antimicrobial peptides, complements, lipid metabolites, etc.) and phagocytes (e.g., granulocytes, monocytes/macrophages, and dendritic cells). These responses not only function to limit or eliminate non-self substances, but also set the stage for subsequent induction of adaptive immune responses by ensuring the transfer of antigenic information to naive lymphocytes through promoting the activation of antigen-presenting cells, particularly dendritic cells (DCs). Induction of adaptive immune responses results in the generation of antigen-specific antibodies and effector T cells, which contribute to the elimination of non-self substances, and to immunological memory.
Antimicrobial peptides (AMPs) are endogenous peptides and proteins with a direct anti-microbial effect. Chemotactic factors, including classic chemoattractants and chemokines, control the directional migration of cells (including leukocytes) using G-protein-coupled seven-transmembrane domain receptors (GPCRs). Studies in the last couple of years have established that many AMPs, such as defensins, cathelicidins, eosinophil-derived neurotoxin and high-mobility group proteins, are chemotactic for various leukocytes while many chemokines exhibit a direct anti-microbial effect. In addition, certain AMPs and chemokines have been demonstrated to have the capacity to induce DC maturation and to enhance antigen-specific immune responses in mouse models. Our team has proposed to classify those endogenous mediators with dual DC-recruiting and activating effects as 'alarmins' and we have hypothesized that alarmins may play critical roles in alerting the adaptive immunity by enhancing the induction of antigen-specific immune responses through promoting antigen uptake, processing and presentation.
Our team believes that the extensive investigation of alarmins, including their number, generation, and mode of action, will help elucidate their roles in immunity, with the hope of modulating immune responses using alarmins as targets. My current research on alarmins focuses on three major areas:
1. Identification of additional alarmins. Alarmins have been identified from the defensin, cathelicidin, chemokine, eosinophil-associated ribonuclease, and high-mobility group protein families; however, it is currently unclear whether all the members of these protein families have the properties of an alarmin. For example, within the defensin family (classified into alpha, beta, and theta subfamilies) only a number of beta-defensins have been characterized at the protein level, despite the existence of up to 30 beta-defensin genes in either mouse or human genome. Members of the defensin, chemokine, and high-mobility group protein family are being screened for dual DC-chemotactic and DC-activating properties. Positive hits are tested for DC recruitment and enhancement of antigen-specific immune responses in mouse models for identification.
2. Elucidation of the mechanism(s) by which various alarmins chemoattract and activate DCs. This project includes identifying the receptors used by alarmins for the induction of DC migration and activation, and mapping the corresponding intracellular signal transduction pathways. The receptors responsible for mediating the chemotactic and DC-activating effects of a given alarmin can be different. We have reported that several alarmins induce leukocyte migration using GPCRs (e.g., CCR6 for beta-defensin-2, FPRL1 for human cathelicidin), whereas the receptors mediating the DC-activating effect of mouse beta-defensin-2 and high-mobility group box-1 protein are reported to be the Toll-like receptors TLR4 and TLR2 and/or the receptor for advanced glycation endproducts (RAGE). The receptors of several alarmins, such as eosinophil-derived neurotoxin and defensin-3, are currently under investigation.
3. Testing the potential use of alarmins as adjuvants for experimental tumor immunotherapy. Tumor-bearing individuals, despite the existence of tumor-associated antigen (TAA), often lack a generation of effective TAA-specific anti-tumor immune responses due to the low number of TAA-specific T cells, a deficient or sub-optimal initiation TAA-specific immune response to generate effector and memory T cells, or insufficient migration of effector T cells to tumor sites. One potential reason for inadequate initiation of the TAA-specific T cell response may be due to the lack of alarmin(s) at the tumor tissue so that tumor-infiltrating DCs do not receive a strong maturational signal, resulting in the formation of lymphoid-homing DCs that cannot present TAA to trigger T cell proliferation and clonal expansion. Based on the capacity of alarmins to enhance antigen-specific immune response, we are currently investigating and comparing several alarmins in mouse tumor models to: 1) ensure if they can promote an anti-tumor immune response, and 2) sort out the more potent Th1-polarizing alarmin(s).
This page was last updated on 4/16/2014.