Hamilton Hart Lab
Research Summary:
Our lab studies CD8+ T cells which control infections by intracellular pathogens such as viruses, intracellular bacteria, and parasites by recognizing pathogen-derived peptides presented by MHC class I molecules. Upon encounter with their specific antigen, naive CD8+ T cells proliferate and differentiate into effector T cells, which express cytokines that amplify the immune response and effector molecules that target destruction of infected cells. Following antigen clearance, most CD8+ effector T cells die, but a subset survives and differentiates into a diverse population of long-lived memory T cells that aim to protect the host from reinfection.
The overarching goal of our research is to understand how functional memory T cells are formed, maintained, and respond robustly without causing damaging immunopathology.
NK Cell Regulation of CD8+ T Cells During Malaria
We employ a mouse model that mimics the human experience in development of cerebral malaria, a condition caused by specific malarial strains to which children are particularly vulnerable. During this infection CD8+ T cell populations traffic to the brains of experimental mice. These cells recognize antigen presented by brain endothelial cells and mount an attack, which can cause brain hemorrhages. The goal of our studies is to find ways to inhibit or control CD8+ T cell activity in the brain through immune system modulation to prevent cerebral hemorrhaging. We have found that stimulation by IL-15 complexes can dampen the CD8+ T cell response to triggering antigens in the brain. This happens via IL-10 production by NK cells.
Long-Lived Effector Cells (LLECs)
We found that a subset of memory CD8+ T cells that expresses KLRG1 and CX3CR1 does not readily expand after antigen exposure, yet provides very effective clearance of acute infection. We are currently investigating the factors necessary for the maintenance of LLECs, if and how these cells participate in tissue-initiated infections, and the receptor(s) responsible for their function.
'Dirty Mice'
Laboratory strains of mice which are cohoused with pet store mice are exposed to a diverse mixture of microbial organisms. This process causes multiple long lasting changes to the mouse immune system. We find these changes more accurately reflect the human immune system. We are pursuing multiple questions related to the development of T cell immunity following vaccination and infection in this model.
Lab Updates
Congratulations to Erin Lucas on her F32 award from NIAID "Determining factors of inflammation that support the expansion and function of long-lived effector cell CD8 T cells in a mature memory compartment"!
Congratulations to Ben Fisher on completing his T35 summer research project "Investigating IL-15C Mediated Immunosuppression of CD8+ T Cells during Cerebral Malaria"!
