Decoding the immune response to explain human health and disease
The regulation and function of the immune response plays a central role in both infection and cancer. Our laboratory wants to understand how the immune system recognizes, identifies, and responds to antigens. Our work uses a mix of clinical cohorts, computational analyses, and mechanistic studies to look at all facets of the immune response. We want to know what determines whether an immune response is beneficial or harmful and what steps of the immune response we can modify to increase the benefit of therapies.
Our laboratory is interested in deciphering human susceptibility to disease and how the immune response contributes to productive or pathological outcomes. We conduct multiple types of human cohort studies, with a particular focus on pediatric studies of influenza and SARS-CoV-2, to learn about the correlates of protective or pathological immunity. We then translate these insights into mechanistic studies to define the immune response and identify steps we can encourage or inhibit to impact therapeutic intervention against infectious diseases and tumors.
A significant portion of our laboratory is focused on understanding T cell receptor specificity: the rules that a T cell uses to interpret the surrounding world. We are working to define the rules that T cells use to distinguish antigens (viral pathogen, tumor, self) in an effort to construct algorithms to predict recognition and response. T cells respond to viral pathogens like influenza or SARS-CoV-2 by identifying particular pieces of the virus. The size and functional profile of the response mounted may depend on which of these pieces are recognized. Is the response beneficial, and effective, at removing the threat? Or does the response create collateral damage?
We also pursue research related to cancer and tumor immunity. We are interested in exploring what distinguishes effective T cell responses to tumor antigens vs. those that fail to be mounted or are ineffective. Mutations in particular proteins may drive antigen presentation that stimulates a response, even if the resulting protein appears somewhat normal. Our work aims to predict antigen recognition in this, and other, contexts.
Overall, this work on adaptive immunity will help guide our understanding of why immune responses mounted by patients are often ineffective. Identifying the appropriateness of the functional program engaged, or the T cell population recruited and activated, could help improve therapeutic intervention.
Dysregulation of innate immunity, the early first responder to infection or insult, leads to manifestations of disease. Understanding regulation of this system at a hyper-quantitative level will help inform therapeutic development. When otherwise healthy individuals suffer remarkable illness, it is often the result of innate immunity, working to eliminate an insult, but driving tissue-damaging off-target effects or preventing another system from operating properly. We collect well-defined, well-controlled cohorts, from New Zealand, to Los Angeles, to Nicaragua, that allow us to analyze these correlates of disease. We also analyze household cohorts to explore differential susceptibility and response to viral infection.
There is evidence that the very first influenza antigen exposure an individual encounters determines how they’ll respond to subsequent infection over their lifetime. We have recently launched an innovative cohort study enrolling children at birth and following them to at least 7 years of age, in order to explore adaptive immune specificity and imprinting. While the antigen diversity is much broader for influenza, this work can be expanded to an interrogation of coronaviruses and other viral pathogens.
Following his postdoctoral training with Nobel laureate Dr. Peter Doherty, Dr. Paul G. Thomas joined the faculty in the Department of Immunology in 2009. His work has been instrumental in generating new understanding of T cell receptor specificity and defining key elements of innate and adaptive immune responses that determine clinical outcomes to viral infections. Dr. Thomas leads several complex institutional programs including human influenza surveillance efforts and virtual repository development, and currently serves as PI for the 7-year, 12 institution DIVINCI consortium. In addition to his scientific achievements, Dr. Thomas is widely regarded for his mentorship and empowerment of junior scientists.
Empowered research team of computationally-minded molecular and cellular immunologists