Watch immune cells dig tunnels in tissues

White blood cells called cytotoxic T lymphocytes (CTLs) dig tunnels in tissues, potentially allowing other CTLs to quickly reach infected cells and tumor cells, researchers report December 1st in Biophysical Journal. The results show that some CTLs move slowly as they create channels through the extracellular matrix (ECM) - a major component of tissues. Afterward, other CTLs move quickly through the channels, presumably to efficiently search for and eliminate target cells.

"The migration behavior of immune cells, as well as their search strategies in the ECM, are not well understood and are currently of great interest in physics and biology," says senior study author Heiko Rieger of Saarland University. "Our findings suggest that modulating properties of the ECM of tissue would have an impact on the efficiency of the immune response—and might give rise to ideas for new therapeutic strategies in cancer treatment."

CTLs play a key role in eliminating pathogen-infected cells and tumor cells. To find their targets, they have to navigate and migrate through complex biological microenvironments, which are shaped by the ECM. These target cells are often low in number in the early stages of disease development, so the ability of CTLs to quickly search for them is crucial for an efficient immune response.

The ECM mainly consists of proteins called collagens and has essential roles in nearly all cellular functions. In various types of cancer, the collagen network becomes dense, stiff, and highly aligned in the vicinity of tumors, facilitating the transport of cancerous cells and making the ECM an important player in cancer metastasis, invasion, and prognosis. "Understanding the migration and interactions of immune cells in collagen networks is crucial to unravel the underlying details of the immune response and to design effective treatment strategies," Rieger says.

To address this issue, Saarland University researchers mimicked the ECM using 3-D networks with different concentrations of bovine collagen and analyzed the migration trajectories of human CTLs through the matrices using 3-D live cell imaging with lightsheet microscopy. The CTLs showed three different types of motion: slow, fast, and mixed. Mathematical modeling by first author Zeinab Sadjadi suggests that the cells switch between slow and fast states.

Similar movement types have been previously reported for natural killer (NK) cells in collagen in the presence of target cells. NK cells have similar immune functions as CTLs. "The similarity of the characteristics of CTLs and NK cell trajectories points towards a common mechanism for migration of both cell types through collagen networks," Rieger says.

Based on their initial findings, the researchers hypothesized that CTLs move slowly as they push aside and tear apart the collagen fibers to form channels, which facilitate the fast movement of other T cells in the collagen network. Experimental evidence supported this scenario. For example, migrating T cells followed each other on exactly the same track, and cells moved quickly in channel-like cavities within the collagen matrix.

One important limitation of the study is that it used synthetic collagen matrices. Living tissue contains many other components that might influence the migratory behavior of immune cells.

Moving forward, the researchers plan to analyze the long-term impact of T cells on the ECM. They will also examine whether the channels enhance the ability of CTLs to search for target cells in collagen matrices. "Understanding how CTLs migrate in such tissues might lead to new therapeutic strategies in preventing metastasis in early stages of cancer," Rieger says.