Gα13 restricts nutrient driven proliferation in mucosal germinal centers.

in Nature immunology by Hang T Nguyen, Moyi Li, Rahul Vadakath, Keirstin A Henke, Tam C Tran, Huifang Li, Maryam Yamadi, Sriranjani Darbha, Yandan Yang, Juraj Kabat, Anne R Albright, Enoc Granados Centeno, James D Phelan, Sandrine Roulland, Da Wei Huang, Michael C Kelly, Ryan M Young, Stefania Pittaluga, Simone Difilippantonio, Jagan R Muppidi

TLDR

  • The study looked at how a protein called Gα13 helps keep B cells in a specific place called a germinal center. The study found that when Gα13 is missing, it can cause the germinal center to react more strongly and make more of a protein called Myc. The study also found that the missing Gα13 makes B cells more dependent on certain nutrients from food to grow and make more Myc. The study suggests that this could be a way to treat a type of cancer called aggressive lymphoma.

Abstract

Germinal centers (GCs) that form in mucosal sites are exposed to gut-derived factors that have the potential to influence homeostasis independent of antigen receptor-driven selective processes. The G-protein Gα13 confines B cells to the GC and limits the development of GC-derived lymphoma. We discovered that Gα13-deficiency fuels the GC reaction via increased mTORC1 signaling and Myc protein expression specifically in the mesenteric lymph node (mLN). The competitive advantage of Gα13-deficient GC B cells (GCBs) in mLN was not dependent on T cell help or gut microbiota. Instead, Gα13-deficient GCBs were selectively dependent on dietary nutrients likely due to greater access to gut lymphatics. Specifically, we found that diet-derived glutamine supported proliferation and Myc expression in Gα13-deficient GCBs in the mLN. Thus, GC confinement limits the effects of dietary glutamine on GC dynamics in mucosal tissues. Gα13 pathway mutations coopt these processes to promote the gut tropism of aggressive lymphoma.

Overview

  • The study investigates the role of germinal centers (GCs) in mucosal sites and the G-protein Gα13 in regulating their development and function. The study tests the hypothesis that Gα13-deficiency fuels the GC reaction and promotes the gut tropism of aggressive lymphoma. The methodology used includes the study of mice with Gα13-deficiency and the analysis of mucosal tissues and mesenteric lymph nodes (mLNs) for GC dynamics and Myc protein expression. The primary objective of the study is to understand the mechanisms underlying the gut tropism of aggressive lymphoma and to identify potential therapeutic targets for its treatment.

Comparative Analysis & Findings

  • The study found that Gα13-deficiency fuels the GC reaction in mLNs via increased mTORC1 signaling and Myc protein expression. The competitive advantage of Gα13-deficient GC B cells (GCBs) in mLNs was not dependent on T cell help or gut microbiota but on dietary nutrients, specifically glutamine. The study also found that diet-derived glutamine supported proliferation and Myc expression in Gα13-deficient GCBs in the mLNs. The results suggest that GC confinement limits the effects of dietary glutamine on GC dynamics in mucosal tissues. The study also identified Gα13 pathway mutations as potential therapeutic targets for the treatment of aggressive lymphoma.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study highlights the importance of dietary nutrients in regulating GC dynamics and the potential of Gα13 pathway mutations as therapeutic targets for the treatment of aggressive lymphoma. The study also identifies potential future research directions, such as the exploration of other dietary nutrients that may influence GC dynamics and the development of targeted therapies for Gα13 pathway mutations. The study's findings have the potential to advance our understanding of the mechanisms underlying the gut tropism of aggressive lymphoma and to identify new therapeutic options for its treatment.
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