Abstract
Effector T cell migration through tissues can enable control of infection or mediate inflammatory damage. Nevertheless, the molecular mechanisms that regulate migration of effector T cells within the interstitial space of inflamed lungs are incompletely understood. Here, we show T cell migration in a mouse model of acute lung injury with two-photon imaging of intact lung tissue. Computational analysis indicates that T cells migrate with an intermittent mode, switching between confined and almost straight migration, guided by lung-associated vasculature. Rho-associated protein kinase (ROCK) is required for both high-speed migration and straight motion. By contrast, inhibition of Gαi signaling with pertussis toxin affects speed but not the intermittent migration of lung-infiltrating T cells. Computational modeling shows that an intermittent migration pattern balances both search area and the duration of contacts between T cells and target cells. These data identify that ROCK-dependent intermittent T cell migration regulates tissue-sampling during acute lung injury.
Highlights
Effector T cell migration through tissues can enable control of infection or mediate inflammatory damage
The principal goal of this study was to analyze the in situ behavior of effector T cells in intact lung tissue
Analysis of peripheral lymph nodes, where T cells are segregated from the vasculature, revealed that most adoptively transferred GFP+ T cells were negative for the intravascular CD3 stain (CD3−), which indicated that they were extravascular (Fig. 1a, left panel)
Summary
Effector T cell migration through tissues can enable control of infection or mediate inflammatory damage. Computational modeling shows that an intermittent migration pattern balances both search area and the duration of contacts between T cells and target cells These data identify that ROCK-dependent intermittent T cell migration regulates tissue-sampling during acute lung injury. Two-photon studies have shown that lung-infiltrating T cells perform active interstitial migration during infection and asthma, we know very little about the molecular mechanisms that enable tissue-navigation of lunginfiltrating T cells[28,29,30,31]. ROCK on the other hand is crucial for T cells to achieve high speeds and straight migration These data suggest that environmental and cell-intrinsic signals cooperate to enable effective contact-guided tissue-navigation of T cells during acute lung injury
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