| How do blood-borne immune cells navigate the circulation and selectively position themselves among distinct tissue compartments? This question has been the focus of intense study since leukocyte rolling and migration were first described by pathologists in the nineteenth century. Leukocyte trafficking is now understood to be of central importance in the maintenance of systemic immunity, and many of the underlying mechanisms that regulate leukocyte adhesion and recruitment have begun to be elucidated. Yet despite many conceptual advances, the scope of molecular interactions implicated in the trafficking program has proven to be enormously complex and not amenable to simple, reductionist descriptions.;In this thesis, we develop a family of mathematical models describing leukocyte recruitment which provide a natural framework for dissecting increasing levels of biological complexity. This strategy entails three related aims: (1) to identify intrinsic molecular properties that govern adhesion equilibria between leukocytes and their substrates; (2) to define how mechanochemical variations among adhesion receptors affect leukocyte kinematics; and (3) to describe how intracellular signaling events dynamically regulate the transition between equilibrium adhesion states. We first developed a minimal mathematical model and identified physical regimes in which receptor-mediated adhesion is either monostable or bistable. Incorporating more detailed descriptions of receptor mechanochemistry then allowed us to define precise molecular requirements that give rise to shear-enhanced leukocyte rolling. Finally, we constructed a spatio-temporal model of the signaling networks known to activate leukocyte adhesion. By integrating simulations of adhesion and signaling, we recapitulated characteristic dynamics of leukocyte recruitment and predicted a role for combinatorial ligand recognition in generating tissue- and cell-specific homing patterns among heterogeneous populations of T lymphocytes. |
