State Transitions and Feedback Loops in the Immune Response

Job Candidate Talk
Tuesday, February 1, 2011 - 11:00
1 hour (actually 50 minutes)
Skiles 006
University of Utah
The immune system is a complex, multi-layered biological system, making it difficult to characterize dynamically.  Perhaps, we can better understand the system’s construction by isolating critical, functional motifs.  From this perspective, we will investigate two simple, yet ubiquitous motifs:state transitions and feedback regulation.Numerous immune cells exhibit transitions from inactive to activated states.  We focus on the T cell response and develop a model of activation, expansion, and contraction.   Our study suggests that state transitions enable T cells to detect change and respond effectively to changes in antigen levels, rather than simply the presence or absence of antigen.  A key component of the system that gives rise to this change detector is initial activation of naive T cells.  The activation step creates a barrier that separates the slow dynamics of naive T cells from the fast dynamics of effector T cells, allowing the T cell population to compare short-term changes in antigen levels to long-term levels.  As a result, the T cell population responds to sudden shifts in antigen levels, even if the antigen were already present prior to the change.  This feature provides a mechanism for T cells to react to rapidly expandingsources of antigen, such as viruses, while maintaining tolerance to constant or slowly fluctuating sources of stimulation, such as healthy tissue during growth.For our second functional motif, we investigate the potential role of negative feedback in regulating a primary T cell response.  Several theories exist concerning the regulation of primary T cell responses, the most prevalent being that T cells follow developmental programs.  We propose an alternative hypothesis that the response is governed by a feedback loop between conventional and adaptive regulatory T cells.  By developing a mathematical model, we show that the regulated response is robust to a variety of parameters and propose that T cell responses may be governed by a simple feedback loop rather than by autonomous cellular programs.