Principal Investigator: Avery August

DESCRIPTION (provided by applicant): 

Vaccine efficacy depends on strong long-term development of immune memory. CD8+ T cells play critical roles in the immune response to bacteria and viruses, and the development of an effective CD8+ T cell immune response has been intensely investigated. Memory CD8+ T cells develop following antigenic responses over several identifiable phases. Initial antigen or pathogen recognition initiates clonal expansion of naïve T cells, which develop into effector T cells. Upon pathogen or antigen clearance, these effector T cells undergo a drastic contraction phase, with death of a majority of the effector cells, and the development of memory precursor effector cells, which proceed to differentiate into memory T cells. Methods to selectively manipulate this process would greatly enhance tuning the immune response in specific conditions. However, this process is still poorly understood. Three parameters that affect these responses are antigen affinity, T cell receptor (TcR) signal strength and inflammation. Antigen affinity (for TcR) and TcR signal are T cell intrinsic, while inflammation is thought to be T cell extrinsic. How these three parameters intersect to control memory development is unclear. The tyrosine kinase Itk is a pharmaceutically tractable target that regulates TcR signal strength, and our preliminary data suggest that it tunes T cell mediated inflammation, and timing of the development CD8+ memory T cell response. The objective of this application is to determine the role of Itk regulated TcR signal strength and antigen affinity for TcR, in tuning the development of CD8+ effector and memory responses during bacterial infection. We will test the hypothesis that pathways regulated by Itk tune inflammation during CD8+ T cell response, regulating the development of memory CD8+ T cells in response to infection. Our specific aims are: 1) Determine the ability of TCR signal strength to tune antigen affinity induced development of short-term effector and long term memory CD8+ T cells during infection; 2) Determine the mechanism by which of Itk regulates development of MPEC during infection induced memory generation, and 3) Determine the ability of Itk to tune inflammation and thus the development of short-term effector and long-term memory CD8+ T cells during infection. This work is extremely innovative as we have exciting preliminary data that when fleshed out, will provide information on a signaling pathway that could be manipulated to enhance the development of memory T cells, while reducing vaccine induced inflammation. This work is also innovative because we have devised novel approaches to study the impact of this signaling pathway on the development of different phases of the CD8+ T cell response. Furthermore, our work is highly translatable as it could lead to a method to tune the development of CD8+ T cell memory in humans.