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T-cell and B-cell immunodominance

In the arms race between pathogen and host, the adaptive immune system uses a diverse set of pattern detectors to identify and eliminate pathogens and pathogen infected cells. These detectors bind to short contiguous (T-cells, B-cells) and non-contiguous (B-cells) protein fragments called epitopes. During the course of an infection the immune system focuses its response to a small fraction of the thousands of potential targets. This phenomenon, known as immunodominance, is a fundamental property of the adaptive immune response. Understanding the mechanisms that govern immunodominance is crucial for designing vaccines. Immunodominance is a result of a large number of factors including immunological history, antigen processing and presentation, viral load and kinetics of viral expression, and host genetics.

 

Our lab employs systems immunology methodologies to study the underlying mechanisms that govern T-cell and B-cell immunodominance in both natural infection and vaccination. We are developing and using both computational and experimental tools to identify both viral and host features that define and modulate immunodominance hierarchies. The nature of our work is translational, integrating the design and application of computational approaches with clinical and laboratory studies that provide data for validating and refining our computational tools.

 

Inside our body, a battle rages between the immune system and disease-causing pathogens. Striving for an advantage, pathogens constantly evolve to evade detection by the immune system. When viruses infect a cell, they bring their own genetic material into the cell and use cellular resources to propagate. As a result, HLA molecules present viral proteins on the infected cell’s surface, spurring an immune attack on the "odd" cells. 

The adaptive immune system provides long-lasting protection against previously encountered pathogens via memory T cells and B cells that can quickly reactivate upon re-infection, facilitate clearance (T cells) and in many cases provide sterilizing immunity (B cells). Vaccination, the most cost-effective public health intervention, stimulates the adaptive immune system to generate responses towards antigens from a given pathogen 

An adjuvant is a pharmacological and/or immunological agent that are added to vaccines in order to modify the immune response by boosting it such as to give a higher amount of antibodies and a longer lasting protection. While adjuvants have been licensed and used in vaccines for more than a century, only recently have we began to unravel the mechanisms by which they enhance the immune responses to vaccines. 

Children are an at-risk population for developing complications following influenza infection, but immunologic correlates of disease severity are not understood. We hypothesize that innate cellular immune responses at the site of infection would correlate with disease outcome. To test this, we profiled the innate and adaptive immune responses following influenza infection in an observational cohort 

In randomized case-control clinical trials of vaccines, participants are followed over time after randomly being assigned to a placebo or vaccine treatment group. In vaccine efficacy trials, we are now able to sequence the breakthrough viruses of participants who become infected during the course of the trial. The genetic characterization of 'breakthrough viruses' - viruses that evade a vaccine-induced host immune response in vaccine and placebo recipients can provide key insights into vaccine efficacy and subsequent immunogen design. 

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