Integrin activation in the immune system

Modulation of leukocyte adhesiveness is critical to leukocyte function during the immune response. A central paradigm in this phenomenon is represented by integrin activation, which is controlled by inside-out signal transduction mechanisms triggered by selectins, chemoattractants and TcR-bound Ag and facilitated by mechanochemical forces. Integrins are heterodimeric adhesive receptors differently expressed on all leukocyte subtypes. At least two distinct modalities of integrin activation are known, namely conformational changes, leading to increased affinity, and lateral mobility leading to increased valency, both enhancing cell avidity (adhesiveness). Several signal transduction events have been correlated to integrin activation in leukocytes. The complexity of intracellular signaling networks leading to leukocyte integrin activation is likely functional to generate robustness and fine tuning of integrin activation allowing integration of qualitative and quantitative variations of extracellular signals leading to leukocyte-, agonist- and integrin-specific control of adhesion. In this context, the recent modular abstraction proposed for the functional architecture of biological networks may provide a powerful paradigm to understand regulation and specificity of signaling events. Accordingly, pro-adhesive intracellular signaling networks may be organized in regulatory signalosomes, or modules, corresponding to discrete clusters of interacting signaling proteins, with some devoted to context-dependent regulation of specificity and dynamics of integrin activation. The principles and technologies of systems biology, and more specifically of network theory, may help to address this complexity and unveil the inner logic governing leukocyte recruitment during the immune response.