(376b) How Antigen Quality and Quantity Determine T Cell Triggering In Vivo

Search and recognition of invading antigen presented by the peptide major histo-compatibility complex (pMHC) on the surface of dendritic cells in lymph nodes precede the triggering of T cell receptor (TCR) signaling and the subsequent T cell activation. Using computer simulations aided by experimental studies, we studied signaling events as T cells migrate through the lymph node searching for cognate antigen. We showed that the antigen dosage and quality determine whether and when T cells stop migrating and engage dendritic cells in prolonged conjugation to achieve full activation. Our theoretical analyses of the in silico results further identified a consolidated measure of antigen quantity and type, using which the effects of various measures of antigen quantity and quality on the degree of T cell effector response can be collapsed onto one single curve.

Very few cognate pMHC are needed to trigger TCR signaling and effector functions in Vivo. This suggests that T cells may integrate sub-optimal signals from sequential transient contacts with dendritic cells. Such signal integration, however, would require a mechanism for short-term molecular "memory". Recent computational and experimental studies have revealed that positive feedback regulation of membrane-proximal signaling (Ras activation) causes previously stimulated cells to be rapidly triggered upon subsequent weak re-stimulation. We developed a computational model that couples T cell migration with membrane proximal signaling activities triggered by encounters with dendritic cells bearing pMHCs of different affinities, in order to examine the conditions for signal integration to occur via this mechanism. Specific predictions are made regarding how to test whether this mechanism enables signal integration, and its consequences for T cell sensitivity and the role of endogenous peptides during the earliest events in detecting infectious pathogens.