Vivian Chou | Harvard University

 

The immune system plays the crucial role of defending the body against pathogens that can cause dangerous and deadly infections. How the immune system performs this incredible function has spurred numerous research questions, many still unanswered. In a recent study published in Immunity, researchers at the Ragon Institute in Cambridge, MA and their collaborators put to rest some of these long-standing questions by unveiling insights into a key immune process: B cell fate decision.

 

B cells are the part of the immune system responsible for recognizing pathogens and do so by producing antibodies that target antigens, the molecules that comprise pathogens. Therefore, B cells enable the body to destroy invading pathogens. To accomplish this, B cells must “decide” between two possible fates: they can mature into either plasma cells or memory cells. How B cells make this critical decision has remained unclear up until this point.

 

Led by senior author Dr. Facundo Batista of the Ragon Institute and first author Dr. Carlson Tsui of the Francis Crick Institute, researchers have now identified a protein kinase, PKCβ, that plays a pivotal role in B cell fate decisions. Using mouse B cells that lacked PKCβ (Prkc^-/-), the researchers demonstrated that without functioning PKCβ, there are defects in multiple processes that are essential for cell fate decisions.

 

In particular, Prkc^-/-  B cells failed to develop important structures known as germinal centers and did not differentiate into plasma cells. The researchers also found that Prkc^-/- B cells have defects in mTORC1 signaling, a major regulator of cell growth and metabolism.

 

The researchers found changes in several important cellular processes in Prkc^-/- B cells that explain the observed defects. The failure of Prkc^-/- B cells to form germinal centers was found to be related to the inability of the B cells to correctly position antigens, which is normally a crucial step for B cell fate decision. Furthermore, the impaired mTORC1 signaling in Prkc^-/- B cells caused defects in the regulation of the mitochondria, as well as changes in cell metabolism.

 

Importantly, the researchers found that PKCβ is required for the production of heme, an iron-associated protein that is involved in plasma cell differentiation, and also showed that mTORC1 control of heme synthesis affects cell differentiation. Moreover, the researchers identified specific metabolic molecules associated with mTORC1 that are affected in Prkc^-/- B cells, providing further details of how PKCβ regulates B cell differentiation.

 

Altogether, the researchers’ novel findings not only demonstrate the importance of PKCβ in B cell fate decision but also explain the underlying biology in precise detail. By illuminating key mechanisms of B cell biology during the immune response, this study is an exciting step forward in understanding the complexities of the body’s defenses against pathogens.

 

Photo of stained spleen section courtesy of Carlson Tsui.