Mrass, P. | bioRxiv Science

bioRxiv2022

Quantitative analyses of T cell motion in tissue reveals factors driving T cell search in tissues

T cells are required to clear infection, moving first in lymph nodes to interact with antigen bearing dendritic cells leading to activation. T cells then move to sites of infection to find and clear infection. T cell motion plays a role in how quickly a T cell finds its target, from initial naive T cell activation by a dendritic cell to interaction with target cells in infected tissue. To better understand how different tissue environments might affect T cell motility, we compared multiple features of T cell motion including speed, persistence, turning angle, directionality, and confinement of motion from T cells moving in multiple tissues using tracks collected with microscopy from murine tissues. We quantitatively analyzed naive T cell motility within the lymph node and compared motility parameters with activated CD8 T cells moving within the villi of small intestine and lung under different activation conditions. Our motility analysis found that while the speeds and the overall displacement of T cells vary within all tissues analyzed, T cells in all tissues tended to persist at the same speed, particularly if the previous speed is very slow (less than 2 {micro}m/min) or very fast (greater than 8 {micro}m/min) with the exception of T cells in the villi for speeds greater than 10 {micro}m/min. Interestingly, we found that turning angles of T cells in the lung show a marked population of T cells turning at close to 180o, while T cells in lymph nodes and villi do not exhibit this "reversing" movement. Additionally, T cells in the lung showed significantly decreased meandering ratios and increased confinement compared to T cells in lymph nodes and villi. The combination of these differences in motility patterns led to a decrease in the total volume scanned by T cells in lung compared to T cells in lymph node and villi. These results suggest that the tissue environment in which T cells move can impact the type of motility and ultimately, the efficiency of T cell search for target cells within specialized tissues such as the lung.

immunology↗

bioRxiv2022

CXCR4 controls movement and degranulation of CD8+ T cells in the influenza-infected lung via differential effects on interaction and tissue scanning

Effector CD8+ T cell interactions are critical in controlling viral infection by directly killing infected cells but overabundant or sustained activation also exacerbates tissue damage. Chemokines promote the trafficking of effector CD8+ T cells into infected tissues, but we know little about how chemokines regulate the function of CD8+ T cells within tissues. Using a murine model of influenza A virus infection, we found that expression of the chemokine receptor CXCR4 by lung-infiltrating cytotoxic T cells correlated with the expression of the degranulation marker CD107a. Inhibition of CXCR4 reduced activation, adhesion, and degranulation of cytotoxic T cells in vitro and in vivo. Moreover, in live influenza-infected lung tissue, T cells stopped moving in lung regions with high levels of influenza antigen, and CXCR4 was essential for CD8+ T cells to execute this arrest signal fully. In contrast, CXCR4 increased the motility of CD8+ T cells in low-influenza areas of the lung. We also found that CXCR4 stimulated the effector function of lung-infiltrating cytotoxic T cells even after clearance of influenza virus, and inhibition of CXCR4 expedited the recovery of influenza-infected mice, despite delayed clearance of the replication-competent virus. Our results suggest that CXCR4 promotes the interaction strength of cytotoxic T cells in lung tissue through combined effects on T cell movement and interaction with virally infected target cells in influenza infected-lungs.

immunology↗