Dasatinib reversibly disrupts T cell motility and activation in lymph nodes

Dasatinib is a tyrosine kinase inhibitor widely used to treat Philadelphia chromosome–positive leukemias. While it is known to cause transient lymphocytosis by inducing spleen contraction, its impact on the local immune surveillance and lymphocyte behavior within peripheral lymph nodes (LNs) remained poorly understood. This study investigates how dasatinib affects T and B cell motility, LN physiology, and the subsequent activation of CD8+ T cells.

Using preclinical mouse models, the researchers employed intravital two-photon microscopy to visualize lymphocyte behavior in popliteal LNs following dasatinib administration. They assessed motility parameters (speed, meandering index, and arrest coefficient) and investigated the underlying mechanisms, including blood vessel diameter changes and tissue oxygenation levels. Additionally, they used in vitro and in vivo models—including dendritic cell (DC) vaccination—to determine if dasatinib-induced physiological changes, such as transient hypoxia, interfere with CD8+ T cell activation and proliferation.

Dasatinib administration leads to a rapid, transient reduction in the interstitial motility of both T and B cells within LNs. This effect is not primarily due to direct inhibition of T cell chemotaxis, but rather stems from dasatinib-induced vasoconstriction of LN blood vessels. This constriction reduces blood supply, causing temporary hypoxia within the lymphoid tissue. The researchers demonstrated that this process is mediated by the Rho-associated coiled-coil kinase (ROCK) pathway, as pharmacological inhibition of ROCK reversed the hypoxia and restored T cell motility. Crucially, while high peak concentrations of dasatinib can directly inhibit T cell activation in vitro, the transient nature of these physiological disruptions in vivo means that the overall development of a cellular immune response is delayed but not blocked.