Germinal Center Reaction Found to be Orchestrated by Distinct FDC Niches

During the course of an immune response, antibody-producing white blood cells known as B cells migrate to lymphoid tissue and undergo a selection process that promotes the expansion and persistence of B cells that mediate immunity more effectively.

While the success of this process, which occurs in specialized regions called germinal centers, is known to be dependent on interactions between B cells and fibroblastic reticular cells, until recently, key mechanisms by which such stromal cells guide the germinal center reaction were not well known.

Researchers from Kantonsspital St. Gallen in Switzerland have found that B cell selection in the germinal center is supported by distinct niches of fibroblastic reticular cells. Their research provides insight into a fundamental mechanism underlying the generation of an effective humoral immune response and has led to the development of a new genetic model.

“Our research was motivated by the lack of knowledge about the fibroblastic reticular cells that interact with B cells in lymphoid organs,” stated senior author Dr. Burkhard Ludewig.

“The major subset of that class of fibroblastic reticular cells that had been studied so far, is known as follicular dendritic cell (FDC). We started with the hypothesis that FDCs adopt different states according to their spatial position within a lymphoid tissue, and these specialized states orchestrate the functionality of B cell responses.”

“First, we generated a genetic mouse model that would allow the tracking and modification of such B cell interacting fibroblastic reticular cells. Next, we performed inflammatory and genetic perturbations and studied the biological changes in the molecular signature of the cells, their three-dimensional positioning and the functionality of humoral immunity.”

“These parameters were measured by high-resolution confocal microscopy, flow cytometry and single-cell transcriptomics analysis, all using our newly generated genetic model.”

“This is a cross-disciplinary study that has important implications for both the fields of stromal cell immunobiology and B cell biology. For the field of stromal cell immunobiology, our study delivers a new, powerful genetic model for studying the biological function of FDCs, not only in the context of basic immunology, but also in inflammatory and malignant diseases.”

“Here, we used this model to reveal with an unprecedented resolution the molecular and topological signatures of FDCs under steady-state and inflammatory conditions. For the field of B cell immunology, our study demonstrates that the underpinning FDC network is an integral player in the efficient generation of humoral immune responses, extending the two cell paradigm to a three partner interaction.”

​Their findings were recently published in the journal Nature Immunology under the title, “Remodeling of light and dark zone follicular dendritic cells governs germinal center responses.” Moving forwards, the team plans to continue studying the biology of FDCs.

​”We are planning to extend these analyses to other inflammatory conditions and microenvironments, also in the human setting, to assess how the molecular and functional features of FDCs reflect their environment and species,” stated Dr. Ludewig.

“Our take home message is that engaging with immune cells provide much more than a physical scaffold.”

“They are active players in the immune response, and the cross-talk between FDCs and immune cells is a reciprocal relationship that guides both stromal cell specialization and immunological function.”

Learn about the latest research in the field of immunology from ImmunoFrontiers.