The broader microbial environment has a profound impact on the immune system and host resistance to pathogens. However, this aspect of host-microbial interaction is not well understood. To what extent does continuous “tickle” from microbial environment impact host immunity? If many T cells have already been primed by environmental antigens, does the idea of "original antigenic sin" apply to T cells?

YFV vaccine

We seek to uncover how pre-existing memory impacts the potency and durability of CD4+ T cell immunity. We used YFV vaccine as a model to study human primary response to a novel immune challenge and found a substantial number of clonally expanded memory cells that recognize YFV in the absence of exposure to YFV. After vaccination, pre-existing YFV-specific T cell populations with low clonal diversity underwent limited expansion, but rare populations with a reservoir of unexpanded TCRs generated robust responses. These altered dynamics changed the immunodominance hierarchy and resulted in the enrichment of initially rare but higher avidity T cells. These findings revealed a process of T cell repertoire reorganization that favored "best-fit" T cells in an effective vaccine response. We are extending these studies to understand additional aspects of T cell dynamics and how T cell population-level behavior is connected to differentiation and function.

COVID-19 vaccine

COVID-19 has claimed millions of lives and disrupted social infrastructures around the world. Fortunately, several vaccines are highly effective against SARS-CoV-2. However, much remains unknown about the longevity of memory responses in humans. With the emergence of new viral variants, there is also the need to have a flexible type of immunologic memory that is not only long-lasting but can also respond to mutated viruses. We are studying key factors that impact the durability of immunological memory and the breath of protection against actively mutating viruses.