David Masopust, PhD

The Masopust laboratory investigates CD8 and CD4 T cell biology during viral infection, bacterial challenge, and malignancy to define the principles of durable protective immunity. Our group pioneered the concept that memory T cells do not merely circulate in the blood and lymph, but predominantly occupy barrier tissues and solid organs as non-recirculating tissue-resident memory T (TDRM or TRM) cells. Furthermore, to bridge the translational gap between controlled laboratory settings and human immunology, we developed the "dirty mouse" model. By accounting for the profound impact of diverse, natural microbial exposures, this model allows us to study immune system maturation and function in a context that more accurately reflects the human experience. We integrate intravital multiphoton microscopy, single-cell genomics, spatial biology, and advanced cytometry to dissect how T cells survey host tissues, adapt to their environments, and eliminate threats.

Core Focus Areas

• Resident Memory T cell (TDRM/TRM) Biology & Immunosurveillance: Defining the ontogeny, differentiation, and function resident T cells across mucosal interfaces (intestinal, respiratory, reproductive) and solid organs.
• Iterative T Cell Stimulation & Aging: Exploring the absolute limits of T cell lifespan and functional capacity. We recently demonstrated that iteratively stimulated T cells act as "multi-lifetime" cells, surviving well beyond the natural lifespan of a single organism (Soerens et al., Nature 2021). More recently, we discovered that these cells resist immune senescence in response to chronic stimulation and retain the ability to homeostatically migrate through all tissues, offering implications for both the biology of aging and the design of durable cellular immunotherapies.
• Cancer Immunotherapy & Translational Medicine: Exploiting TDRM/TRM immunosurveillance and "alarm" functions to overcome immunosuppressive tumor microenvironments. We are actively translating these basic discoveries into the clinic, including an open clinical trial evaluating peptide alarm therapy—a strategy that intentionally triggers pre-existing resident T cells within solid tumors to recruit and activate a robust, broader anti-tumor immune response (NCT05338658).
• Vaccine Development & Prime-Boost Strategies: Leveraging heterologous prime-boost regimes to optimize T cell memory compartment size, localization, and quality—with a continuing focus on establishing protective mucosal immunity against recalcitrant pathogens including HIV/SIV and influenza virus.