Understanding immune cell movement and activation in tissues

In adult tissues, immune cells encounter a broad range of ECMs, including basement membranes (BMs) and collagen-rich interstitial matrices, which vary largely in the specific biochemical composition and topology. Over the last two decades, it was realized that the mechanics of immune cells (but also other cells, e.g. cancer cells) in physiological, three-dimensional (3D) tissue environments can fundamentally differ from the migration strategies used by cells on two-dimensional (2D) surfaces (Lämmermann and Sixt, Curr Opin Cell Biol 2009; Lämmermann and Germain, Sem Immunopathol 2014). Thus, analyses in native 3D-matrices are indispensable for migration studies to reflect influences by physical properties and geometry of the extracellular surrounding, in particular the ECM. For example, immune cells can switch to an integrin-independent mode of migration in 3D matrices and confined environments (Lämmermann et al., Nature 2008). In contrast, several types of tissue-resident immune cells depend on integrin-mediated adhesion for their tissue dynamics and migration (Kaltenbach et al., Nat Immunol 2023; Paterson & Lämmermann, eLife 2022). Thus, there is a requirement to study cell migration within the physiological context of tissues, where BMs, interstitial matrices and interspersed cells form 1D fibers, 2D surfaces, confined spaces, fibrillar 3D networks, elastic and stiff substrates in close proximity. Still, it is poorly understood how all these variables are integrated to shape the behaviour of migratory cell types and in reverse, how cells shape their environment during migration. To overcome current experimental limitations to directly visualize ECM components and immune cell activation states in tissues, we collaborate with several research groups to develop, characterize and apply novel tools and approaches for the visualization of immune cell dynamics in physiological 3D tissue environments (Mihlan et al., Annu Rev Cell Dev Biol 2022).

Immune cell movement in tissues occurs within a geometrically complex environment that is characterized by basement membranes (red) and fibrillar matrices (not stained here). Immune cell subsets use different strategies to move, navigate and position inside the interstitial space of tissues, such as here the connective tissue of the skin dermis.

© Tim Lämmermann