Xiaoyu Hu’s team from Tsinghua University unveils new function of mast cells
Source：Xiaoyu Hu
2024-06-14
Compared to many highly-studied immune cells, mast cells have been relatively neglected in immunological research in recent years. Studies on mast cell functions are often limited to traditional paradigms, such as the common equivalence of mast cell function with IgE-mediated degranulation found in immunology textbooks and review articles. However, mast cells evolved more than 200 million years before the earliest adaptive immune systems, suggesting they must have functions independent of IgE, which may be fundamental to their existence.
On April 12, 2024, Xiaoyu Hu’s research group at the Institute for Immunology, Tsinghua University published a paper titled “Intraepithelial mast cells drive gasdermin C-mediated type 2 immunity” in the journal Immunity. This study examined a unique population of mast cells colonizing the intestinal epithelium, revealing their significant role in type 2 immune responses. It detailed their interactions with epithelial cells and how they activate the Gasdermin C protein in epithelial cells, thereby mediating the secretion of the key cytokine IL-33.
As early as 1919, a German pathologist observed mast cells embedded between epithelial cells in the intestinal epithelium of animals such as cats, dogs, and sheep. However, the functions of these epithelial-residing mast cells remained unknown. Hu’s group, while studying type 2 immune responses using a parasitic infection model, also observed these intraepithelial mast cells (IEMCs). Using molecular markers such as β7 integrin, they successfully isolated IEMCs from the intestines and analyzed their gene transcriptomes and epigenetic characteristics, indicating these cells might actively participate in cell-cell interactions. These molecular profiling results were consistent with the in vivo localization of IEMCs, prompting further research on IEMC-epithelial cell interactions. They discovered that IEMCs can form nanotubes to transfer specific substances like the unique protease Mcpt1 to epithelial cells, enabling direct interaction. Notably, this interaction does not depend on IgE and can be fully reconstructed in an in vitro co-culture system containing only IEMCs and epithelial cells.
A key question then was the biological function of the substances transferred by IEMCs to epithelial cells. In-depth research revealed that IEMCs can mediate the cleavage and activation of the Gasdermin C (Gsdmc) protein within intestinal epithelial cells. In mice lacking mast cells, Gsdmc could not be cleaved in epithelial cells. Detailed molecular mechanism studies showed that Mcpt1, an enzyme highly expressed in IEMCs, can cleave Gsdmc when co-incubated with the Gsdmc protein. Using Mcpt1 knockout mouse models, they found that the absence of Mcpt1 partially inhibited the cleavage of Gsdmc. Immunologically, IEMC-mediated Gsdmc activation promotes the release of the type 2 immunity key cytokine IL-33 from epithelial cells, which activates ILC2s, ultimately enhancing type 2 immune responses in the gut. These results revealed at least one protease in vivo with Gsdmc-cleaving activity and explained the mechanism by which Gsdmc is activated in physiological processes.
Overall, these studies, which combine immunological mechanisms with biochemical approaches, reveal a new role for mast cells. Specifically, the interaction between intraepithelial mast cells (IEMCs) and epithelial cells is an indispensable component of type 2 immune responses in the gut. This research provides new insights into mast cells and their associated type 2 immune response mechanisms. The currently published research is just the beginning. Mast cells, which have evolved over more than 600 million years, still have many unknown aspects waiting to be explored. Utilizing modern advanced technologies to re-understand and redefine these ancient cells is imperative, and it is believed that more exciting discoveries will emerge in the near future.
This research was completed through close collaboration between Xiaoyu Hu’s team at Tsinghua University and Feng Shao’s team at the National Institute of Biological Sciences. Professor Xiaoyu Hu is the corresponding author of this paper. Postdoctoral researchers Liu Yang from Hu’s group and Huabin He from Shao’s group are co-first authors of the paper. The study received strong support from Professor Wanli Liu of the School of Life Sciences/Institute for Immunology at Tsinghua University. The research was funded by the Ministry of Science and Technology, the National Natural Science Foundation of China, the Tsinghua-Peking Center for Life Sciences, the Institute for Immunology at Tsinghua University, and the Guangzhou National Laboratory.
Links: https://linkinghub.elsevier.com/retrieve/pii/S1074761324001389
On April 12, 2024, Xiaoyu Hu’s research group at the Institute for Immunology, Tsinghua University published a paper titled “Intraepithelial mast cells drive gasdermin C-mediated type 2 immunity” in the journal Immunity. This study examined a unique population of mast cells colonizing the intestinal epithelium, revealing their significant role in type 2 immune responses. It detailed their interactions with epithelial cells and how they activate the Gasdermin C protein in epithelial cells, thereby mediating the secretion of the key cytokine IL-33.
As early as 1919, a German pathologist observed mast cells embedded between epithelial cells in the intestinal epithelium of animals such as cats, dogs, and sheep. However, the functions of these epithelial-residing mast cells remained unknown. Hu’s group, while studying type 2 immune responses using a parasitic infection model, also observed these intraepithelial mast cells (IEMCs). Using molecular markers such as β7 integrin, they successfully isolated IEMCs from the intestines and analyzed their gene transcriptomes and epigenetic characteristics, indicating these cells might actively participate in cell-cell interactions. These molecular profiling results were consistent with the in vivo localization of IEMCs, prompting further research on IEMC-epithelial cell interactions. They discovered that IEMCs can form nanotubes to transfer specific substances like the unique protease Mcpt1 to epithelial cells, enabling direct interaction. Notably, this interaction does not depend on IgE and can be fully reconstructed in an in vitro co-culture system containing only IEMCs and epithelial cells.
A key question then was the biological function of the substances transferred by IEMCs to epithelial cells. In-depth research revealed that IEMCs can mediate the cleavage and activation of the Gasdermin C (Gsdmc) protein within intestinal epithelial cells. In mice lacking mast cells, Gsdmc could not be cleaved in epithelial cells. Detailed molecular mechanism studies showed that Mcpt1, an enzyme highly expressed in IEMCs, can cleave Gsdmc when co-incubated with the Gsdmc protein. Using Mcpt1 knockout mouse models, they found that the absence of Mcpt1 partially inhibited the cleavage of Gsdmc. Immunologically, IEMC-mediated Gsdmc activation promotes the release of the type 2 immunity key cytokine IL-33 from epithelial cells, which activates ILC2s, ultimately enhancing type 2 immune responses in the gut. These results revealed at least one protease in vivo with Gsdmc-cleaving activity and explained the mechanism by which Gsdmc is activated in physiological processes.
Overall, these studies, which combine immunological mechanisms with biochemical approaches, reveal a new role for mast cells. Specifically, the interaction between intraepithelial mast cells (IEMCs) and epithelial cells is an indispensable component of type 2 immune responses in the gut. This research provides new insights into mast cells and their associated type 2 immune response mechanisms. The currently published research is just the beginning. Mast cells, which have evolved over more than 600 million years, still have many unknown aspects waiting to be explored. Utilizing modern advanced technologies to re-understand and redefine these ancient cells is imperative, and it is believed that more exciting discoveries will emerge in the near future.
This research was completed through close collaboration between Xiaoyu Hu’s team at Tsinghua University and Feng Shao’s team at the National Institute of Biological Sciences. Professor Xiaoyu Hu is the corresponding author of this paper. Postdoctoral researchers Liu Yang from Hu’s group and Huabin He from Shao’s group are co-first authors of the paper. The study received strong support from Professor Wanli Liu of the School of Life Sciences/Institute for Immunology at Tsinghua University. The research was funded by the Ministry of Science and Technology, the National Natural Science Foundation of China, the Tsinghua-Peking Center for Life Sciences, the Institute for Immunology at Tsinghua University, and the Guangzhou National Laboratory.
Links: https://linkinghub.elsevier.com/retrieve/pii/S1074761324001389
