Cell Distance Mapping Identifies Functional T Follicular Helper Cells in Inflamed Human Renal Tissue

Visualizing and quantifying the spatial relationships between T and B cells identifies adaptive immune cell networks in human inflammation. Putting Human Inflammation on the Map B cells cannot fight infection by antigen stimulation alone—they need help from T cells. In mice, two-photon electron microscopy has demonstrated that T follicular helper (TFH) cells are critical for providing B cell help in germinal centers. However, it has remained unclear whether—and if so, how—TFH cells provide B cell help in humans. Now, Liarski et al. report that cell distance mapping (CDM) can be used to demonstrate cognate TFH-mediated B cell help in the context of human inflammation. CDM is a computational tool that quantifies spatial relationships between different cell types in tissue. The authors used CDM to measure the internuclear distances between TFH and B cells in inflamed human tissues. They were able to discriminate between noncognate and cognate interactions, which are required for providing help. They also characterized cognate-competent TFH cells and found that they expressed Bcl-6 and IL-21. This technique should be generalizable to diverse antigen presentation and immune cell interactions and, if so, should enhance our knowledge of the immune system in situ. T follicular helper (TFH) cells are critical for B cell activation in germinal centers and are often observed in human inflamed tissue. However, it is difficult to know if they contribute in situ to inflammation. Expressed markers define TFH subsets associated with distinct functions in vitro. However, such markers may not reflect in situ function. The delivery of T cell help to B cells requires direct cognate recognition. We hypothesized that by visualizing and quantifying such interactions, we could directly assess TFH cell competency in situ. Therefore, we developed computational tools to quantify spatial relationships between different cell subtypes in tissue [cell distance mapping (CDM)]. Analysis of inflamed human tissues indicated that measurement of internuclear distances between TFH and B cells could be used to discriminate between apparent cognate and noncognate interactions. Furthermore, only cognate-competent TFH cell populations expressed high levels of Bcl-6 and interleukin-21. These data suggest that CDM can be used to identify adaptive immune cell networks driving in situ inflammation. Such knowledge should help identify diseases, and disease subsets, that may benefit from therapeutic targeting of specific T cell–antigen-presenting cell interactions.

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