Vα14 invariant natural killer T (Vα14iNKT) cell is a unique subset of thymic-derived innate T cells that express T cell receptor (TCR) and NK cell markers. Unlike conventional T cells, Vα14iNKT cells respond to glycolipid antigen presented by CD1d expressed on antigen presenting cells (APCs). Several studies have reported important protective roles for activated Vα14iNKT cells during viral infections by replication-competent viruses. Vα14iNKT cell activation during viral infection occurs through host lipids presented by CD1d or by a TCRindependent mechanism involving Toll-like receptors (TLRs). TLRs are pathogen recognition receptors that play a critical role in initiating the innate immune response to microbes. Among the TLRs, TLR7, TLR8 and TLR9 sense viral signals and can stimulate APCs to induce Vα14iNKT cell activation during viral infections by replication-competent viruses. The potential role of TLR3, also a viral signal sensor, in mediating Vα14iNKT cell activation during acute viral infections are not known, and is therefore a focus of this proposal.
In specific aim #1, our innovative studies will utilize molecular and immunological tools to evaluate the contribution of TLR3 to Vα14iNKT cell activation during acute viral infections.
In specific aim #2, we will examine the functional consequences of Vα14iNKT cell activation via TLR3 signaling on the innate immune response during acute viral infection. Replication-defective Adenoviruses are the most widely studied and used replication-defective vaccine vectors. Replication-defective Adenoviruses are important probes of the host immune response. They help define the first round of infected cells in host immune responses as well as the mechanism of activation of the innate immune response. Therefore, this virus is the obvious choice to use in our studies to evaluate the potential diversity in Vα14iNKT cell activation and function in the presence and absence of acute viral replication. Our preliminary studies have identified a novel and important biological role for TLR3 as a potential mediator of Vα14iNKT cell activation during acute viral infection. Specifically, in response to replication-defective Adenovirus infection in mice, TLR3 negatively regulates Vα14iNKT cell activation. In contrast, TLR3 positively regulates Vα14iNKT cell activation during replication-competent Adenovirus infection in mice. These preliminary findings provide support for a key part of our hypothesis that TLR3 differentially regulates Vα14iNKT cell activation in the presence and absence of acute viral replication to differentially alter the innate immune response. Overall, our studies will advance basic immunological knowledge by providing novel strategies/insights for manipulating Vα14iNKT cell activation. Valuable information obtained from our studies will enhance the development of replication-defective Adenovirus as vectors for gene therapy and vaccines. Moreover, these vaccines may one day be used for the prevention of devastating diseases by replication-competent viruses including HIV, Influenza A virus and herpes simplex virus.
Globally, viral infections such as HIV, Influenza virus and hepatitis C virus are public health concerns and are associated with significant morbidity and mortality. Annually, it is estimated that more than 30 million individuals in the US are susceptible to one or more types of viral infections. In addition, the annual direct and indirect costs of viral infections in the US is over $500 million. Vaccines are important discoveries of medicine because of their ability to reduce morbidity and mortality. The ability to elicit a host immune response that protects against viral diseases has been the standard for viral vaccines including smallpox, hepatitis B, influenza and chickenpox. Traditionally, viral vaccines have been one or two types, the first being inactivated whole virus while the second is live-attenuated viruses. However, for some viruses such as HIV and herpes simplex virus, these classical approaches to vaccines are not successful. Replication-defective viral mutant strains provide a new form of viral vaccine that are superior to conventional vaccines. Therefore, replication-defective viruses have potential use as vaccines and as a vector for gene therapy. Replication-defective Adenoviruses are the most widely studied and used replication-defective vaccine vectors. Therefore, this virus is the obvious choice to use in our studies to define the potential diversity in function of the innate immune T cell, Vα14iNKT cells, during acute viral infection. Specifically, mice infected with replication-competent and replicationdefective Adenoviruses will be used to evaluate both the mechanisms of Vα14iNKT cell activation as well as the biological activities of activated Vα14iNKT cells. Collectively, our research will advance basic immunological knowledge and provide insights for manipulating the biological activities of activated Vα14iNKT cells during acute viral infection by replication-competent and replication-defective Adenoviruses. Our studies will definitely yield valuable information that will enhance the development of replication-defective viruses as vectors for gene therapy and vaccines for prevention/treatment of viral infections including HIV, Influenza virus and herpes simplex virus.
| Downs, Isaac; Liu, Jianfeng; Aw, Tak Yee et al. (2012) The ROS scavenger, NAC, regulates hepatic V?14iNKT cells signaling during Fas mAb-dependent fulminant liver failure. PLoS One 7:e38051 |
| Downs, Isaac; Aw, Tak Yee; Liu, Jianfeng et al. (2012) V?14iNKT cell deficiency prevents acetaminophen-induced acute liver failure by enhancing hepatic glutathione and altering APAP metabolism. Biochem Biophys Res Commun 428:245-51 |
| Ajuebor, Maureen N; Chen, Qingling; Strieter, Robert M et al. (2010) V(alpha)14iNKT cells promote liver pathology during adenovirus infection by inducing CCL5 production: implications for gene therapy. J Virol 84:8520-9 |
