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Monday, April 15, 2013
We live in a world full of invisible friends and enemies; a world full of microorganisms that can harm us or help us. Everyday, inside our bodies, hundreds of battlesand ceasefires are taking place, all under the control of our immune system.
The immune system is a network composed of different cell types, receptors, and signaling pathways that respond to pathogens while remaining tolerant to “self” and commensal microflora. Understanding how the immune system responds, and when it malfunctions, can give us the ability to control, treat and prevent a number of inflammatory and infectious diseases.
The discovery of pathogen recognition receptors (PRRs) and dendritic cells expanded our knowledge of the immune system by establishing connections between innate immune signaling and adaptive immunity. My fundamental scientific goal is to understand how the innate immune signaling network regulates and shapes our adaptive immune responses. I find dendritic cells (DCs) to be an excellent model to study the immune signaling networkbecause theyare important phagocytic antigen-presenting cells that sense pathogens through PRRs, such as Toll-like receptors (TLRs) orNod-like receptors (NLRs), and alsoactivate naive T cells responses.
DCs connect the innate and adaptive immune responses,since the activation state of the DC determines the type of immune response that gets triggered. Although it is evident that innate immune receptors on DCs are required for optimal immune activation, the mechanisms by which these receptors regulate the functioning of DC have not yet been fully revealed. What is clear is that, in response to a variety of stimuli, DCs change from immature cells specialized for antigen capture into mature cells specialized for T cell stimulation.Thus a fundamental question is how the signaling network downstream of TLRs, NLRs and other innate immunity receptors regulate DCs,and hence, activatesthe types of T cell responses required to fight infections.
My introduction to immunology was through vaccine adjuvants- immunologist’s “dirty little secret”. While working on my PhD project I found that, after taking in aluminum adjuvants, DCs induce T cell differentiation into Th2 cells in a caspase-1-dependent manner (1). At the same time, caspase-1 activation by aluminum adjuvants is critically dependent on an intracellular innate immune signaling system called the NLRP3 inflammasome. This work established a good example of a connection between innate and adaptive immunity through DCsand got me interested in vaccine development and adjuvant function of innate immune ligands.
My research on adjuvantslead me to study how innate immune receptors regulate the specific functions of DCs, and how transcriptional and local post-translational modifications induced by innate immune signals in these phagocytes sculpt appropriate T cell responses. To pursue my interests in the phagocyte biology and innate immune signaling, I began my postdoctoral work at the MGHfCDevelopment Immunology Laboratory with a great mentor, Lynda Stuart. I consider myself very lucky to be able to work with Dr. Stuart and learn from her. The laboratory gave me a great opportunity to expand my research skills and approaches and learn about many aspects of host-pathogen interactions, host defense and biology of phagocytosis.
Our work in the laboratory helped us obtain important insights on phagocytosis.The phagosome is a complex intracellular organelle that destroys internalized pathogens. Another function of the phagosome is to provide a spatially compartmentalized platform to generate ligands for PRRs for the initiation of innate immune signaling and antigen presentation. We showed that TLR-dependent recognition of S. aureus in macrophages requires phagosome acidification and maturation (2). Yet, the innate immune signals determining phagosome acidification and maturation are not fully known.
We have discovered a novel role of the inflammasome in innate immunity, which is independent of its role in IL-1? and IL-18 secretion. We found that the NLRP3 inflammasome and caspase-1 regulatethe microbicidal activity of phagosomes containing Gram-positive bacteria. Specifically, we have observed that caspase-1 becomes active early during S.aureus phagocytosis through an NLRP3- and ASC- dependent pathway. Active caspase-1 accumulates on S.aureus phagosomes and directly regulates phagosome pH (Figure 1). Macrophages lacking NLRP3, ASC and caspase-1 are unable to acidify the phagosomes containing Gram-positive microbes (Figure 2). We have identified a number of phagosome- associated caspase-1 substrates. One of these substrates is NADPH oxidase (NOX2). We confirmed that caspase-1 cleaves NOX2, inactivating it and promoting phagosome acidification. In contrast,the absence of active caspase-1 leads to phagosomes with elevated NOX2 activity, retarded acidification and impaired microbial killing.Thisnovel function of NLRP3/ caspase-1 in cellular defense provides insight into a mechanism by which innate immune signals act to modify the function of phagosomes (3).
I would like to apply the knowledge I gained in Dr. Stuart’s lab to look at DCs. I am very interested in the interface between innate and adaptive immunity: how DCs instruct T cells and how innate immune signals shape activation program in DCs. Our discovery of the novel cell autonomous role of the inflammasome and caspase-1 in the regulation of phagosome function gives us a unique opportunity to look beyond IL-1ß and IL-18 production in the development of the adaptive immune responses. Several main functions of phagosome, which depend on caspase-1 activation and acidification, are antigen presentation, innate immune signaling and microbial killing. The first two of them are extremely important for the development of adaptive immunity. In my next project I would like to investigate the novel role of the inflammasomein DCs to better define the contribution of inflammasome to antigen presenting abilities and maturation state of DCs.By focusing on the mechanism by which active caspase-1 shapes phagosome as an antigen presenting and signaling compartment, we will be able to understand how NLRs through activation of inflammasome affect the development of adaptive immunity (Figure 3).
This project will allow us to establish the molecular mechanism of cell autonomous caspase-1 function in DCs, which directly controls DC-T cell interplay and deepenour understanding of the molecular mechanisms of protection by establishing a new link between innate immune signaling and adaptive immune responses. Our ultimate goal is to understand how the network of innate immune receptors shapes T cell differentiation and the development of adaptive immunity using DCs as a critical control point connecting innate and adaptive systems. Knowing these mechanisms will allow us to understand how DCs sense pathogens and structure their response to drive appropriate T cell activation and how pathogens by manipulating DC maturation divert away from protective adaptive immunity.It will provide better insight into how PRRs regulate antigen processing and priming of naïve T cell responses to pathogens. Additionally, it will help identify specific molecular targets that can aid rational vaccine design and development of adjuvants tailored to drive specific immune responses.
1. Sokolovska A, Hem SL, HogenEsch H. 2007. Activation of dendritic cells and induction of CD4+ T Cell differentiation by aluminum-containing adjuvants. Vaccine.25 (23):4575-85.2. Ip WK*, Sokolovska A*, Charriere GM, Boyer L, Dejardin S, Cappillino MP, Yantosca LM, Takahashi K, Moore KJ, Lacy-Hulbert A, Stuart LM. 2010.Phagocytosis and phagosome acidification are required for pathogen processing and MyD88-dependent responses to Staphylococcus aureus.J Immunol.184(12):7071-81.3. Sokolovska A*, Becker CE*, WK Eddie Ip, Rathinam V, Brudner M, Paquette N, Tanne A, Vanaja SK, Moore KJ,Fitzgerald K, Lacy-Hulbert A and Stuart LM. Activation of caspase-1 by the NLRP3 inflammasome regulates NOX2 to control phagosome function. 2013. Nature Immunology. In press.*Joined first author
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