Pathology

E-mail: matthew.williams@path.utah.edu
Address: 2600B JMRB
Phone: 585-2487

Invading Viral or Bacterial Pathogen

Following recognition of an invading viral or bacterial pathogen, antigen-specific T cells undergo several stages of differentiation.  First, they undergo a rapid proliferative burst, dividing as many as 20 times in less than a week.  Second, they become “effector” T cells, acquiring the ability to eradicate the pathogen either through secretion of cytokines or direct killing of infected cells.  Lastly, a subset of “effector” T cells further differentiates into long-lived memory cells, capable of responding to further challenges with the same or a related pathogen.  My current research is focused on understanding the signals during the initial immune response that promote the ability of a subset of responding T cells to differentiate into memory cells.  Recent data from my lab suggests that the strength of the signal that antigen-specific T cells receive through their T cell receptor (TCR) during the primary response promotes not only their differentiation into memory but also their longevity during the memory phase.  We hypothesize that T cells bearing TCRs with high avidity for antigen are preferentially recruited into the memory compartment.  To formally test this hypothesis, we propose to characterize the TCR repertoire of antigen-specific T cells during the primary response and at memory time points.  The proposed project will consist of sequencing and cloning antigen-specific TCRs at the peak of the initial response (day 8 after viral infection) and at memory time points (days 30-60 after viral infection).  Cloned TCRs will be reintroduced into T cells via a retroviral vector and tested for their avidity for viral antigen.  We predict that antigen-specific TCRs cloned at memory time points will have a higher avidity for antigen than those cloned during the primary response, thus indicating that the strength of the TCR signal is one determining factor in memory differentiation.  Alternatively, the TCR repertoires at each time point may be similar, indicating that TCR signal strength is not a primary factor promoting memory T cell development.

1/2008