Tuberculosis(TB), caused by the organism M. tuberculosis (Mtb) kills more than 2 million people worldwide every year. Our limited understanding of how vaccine responses mediates protection in the lung remains a major hurdle to successful vaccine design against TB. The protective immune response to TB has conventionally been associated with the appearance of CD4+ T helper cells that produce the cytokine interferon gamma (IFN-?), and activates macrophages to control Mtb. We have recently identified that in addition to the IFN-? producing population, a second population of vaccine-induced CD4+ T helper cells that - produce the cytokine interleukin (IL)-17, is key for protection against TB. Subcutaneous immunization of mice with a defined immunodominant IAb-restricted peptide from the Mtb 6kDa Early Secretory Antigenic Protein (ESAT-61-20) in an adjuvant induces both antigen-specific IFN-?-producing and IL-17-producing memory cell populations. However, only the IL-17-producing cells populate the lung while the IFN-?-producing cells are found in the secondary lymphoid organs. The lung-resident memory cells upon exposure to Mtb, produce IL-17 and trigger local expression of chemokines in the lung. This chemokine gradient then attracts protective IFN-?- producing memory cells from the circulation. The arrival of the IFN-?-producing memory cells in the lung and production of IFN? then activates macrophages to halt Mtb growth. Importantly, in the absence of the IL-17 recall response, the accelerated IFN-? memory response does not occur and protection is lost. A majority of approaches to the development of new TB vaccines have focused on subcutaneous route of antigen delivery. However more recently, mucosal immunization has been shown to be more protective upon challenge with virulent Mtb than other routes of immunization. This is consistent with the hypothesis that immunization at the mucosal sites generates superior protection against mucosal infectious diseases. However, the immune mechanisms underlying enhanced protection by respiratory mucosal immunization against TB remains unexplored. Most studies that have used mucosal immunization against Mtb have studied the generation of IFN? responses as a readout of immune activation. However, our recent discovery that IL-17-producing memory cells generated by subcutaneous immunization are a critical component of vaccine-induced protection against TB leads us to raise several basic questions about the induction of IL-17 responses by mucosal immunizations.
In Aim One, we will determine whether mucosal immunization generates protective lung- resident IL-17-producing memory cells and whether altering the adjuvant and including mucosal coadjuvants will generate more effective IL-17 memory responses.
In Aim Two, we will characterize the antigen presenting cells that prime T cell populations and we will define the inductive sites of T cell priming following mucosal immunization.
The aims of the current proposal will promote rational development of mucosal vaccine strategies with the long term goal of improving immunization strategies against Mtb. Tuberculosis(TB), caused by the organism M. tuberculosis (Mtb) kills more than 2 million people worldwide every year, the major hurdle to successful vaccine design against TB is our poor understanding of the requirements for early memory responses to TB in the lung. The need to improve immunization strategies against TB makes it important for us to understand the basic requirements for induction of long-lived effective immunity in the lung against TB. The relevance of this work to public health is that it will promote rational development of mucosal vaccine strategies and will therefore have the potential to reduce the incidence of TB.
Tuberculosis(TB), caused by the organism M.tuberculosis (Mtb) kills more than 2 million people worldwide every year, the major hurdle to successful vaccine design against TB is our poor understanding of the requirements for early memory responses to TB in the lung. The need to improve immunization strategies against TB makes it important for us to understand the basic requirements for induction of long-lived effective immunity in the lung against TB. The relevance of this work to public health is that it will promote rational development of mucosal vaccine strategies and will therefore have the potential to reduce the incidence of TB.
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