Paul Thomas Lab

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.