Genetic control of immune cell proliferation

April 19, 2017

Germinal centers are transient structures in the lymph nodes where antibody-producing B cells proliferate and differentiate at extraordinary rates. Germinal centers can be visually divided into a dark zone and light zone. For the proliferation and differentiation to occur, B cells must cycle between the two zones. Investigators at the Immunology Frontier Research Center (IFReC), Osaka University have discovered how specific genes regulate this cycling. The findings, which can be read in the Journal of Experimental Medicine, provide new insights on how certain types of lymphomas form.

To understand how B cells cycle in the germinal center, Prof. Tomohiro Kurosaki, who led the project, set his eyes on Foxo1.

"Foxo1 is a tumor suppressor gene, but it promotes B cell proliferation in the germinal center," he said.

Normally, the suppression of Foxo1 expression enables cells to proliferate. Even B cells outside the germinal center will proliferate when Foxo1 is suppressed. However, some lymphomas are associated with activated Foxo1, and Kurosaki and his team observed that inside germinal centers, B cells with Foxo1 suppressed will actually lower in numbers.

Transferring the mutant B cells into mice, the researchers further showed that Foxo1 has a vital role in the cycling of B cells between light and dark zones.

"We found B cells remained in the light zone," said Kurosaki of the Foxo1-deficient B cells.

The dark zone is where B cells undergo proliferation. When in the light zone, B cells are selected by follicular helper T (TFH) cells for migration to the dark zone. Kurosaki found that without Foxo1, B cells are not selected at all.

"Knocking out Foxo1 reduced the expression of BCR," he said.

BCR, or B cell receptors, describe the unit on the B cell that binds to the invasion and from which B cells are selected to proceed with the cycling. Moreover, even if the Foxo1-deficient B cells could be manipulated to be selected by the TFH cells, they still did not proliferate, suggesting another factor besides Foxo1 is also imperative to cycling.

Kurosaki's team noticed that the knockout of Foxo1 also led to a reduction in BATF expression in B cells. Reviving the BATF levels recovered the proliferation of Foxo1-deficient B cells in the germinal center. Thus, the proliferation deficiency could be the result of poor crosstalk between the two genes.

The findings provide important new knowledge on antibody production by the body and also the development of certain cancers.

"Even though Foxo1 is a tumor suppressor gene, paradoxically its activity is associated with lymphomas," said Kurosaki. This study provides new candidate molecular targets for the treatment of such lymphomas.
-end-


Osaka University

Related Lymphomas Articles from Brightsurf:

Stop Livin to make lymphoma cells stop living
Researchers at the University of Tsukuba have shown that the protein Livin, an inhibitor of apoptosis or programmed cell death, mediates resistance to immunotherapy in some lymphoma variants.

The Josep Carreras Institute identifies a marker of poor evolution in Hodgkin's lymphoma
Dr. Manel Esteller, director of the Josep Carreras Leukemia Research Institute, published today in Blood journal, the discovery of a marker that allows predicting which patient with Hodgkin's lymphoma will present the aggressive clinical course, and will therefore be a case of special risk.

Geography of childhood cancer in Switzerland studied
A research group under the direction of the Institute of Social and Preventive Medicine of the University Bern has investigated the spatial distribution of childhood cancer risks in Switzerland for the period 1985-2015.

Old weapon, new target: Dasatinib against angioimmunoblastic T-cell lymphoma
Researchers from the University of Tsukuba have shown by in vivo experimentation on a mouse model that angioimmunoblastic T-cell lymphoma is highly dependent on T-Cell Receptor Signaling.

New front opened in fight against common cancer driver
Australian researchers have revealed a new vulnerability in lymphomas that are driven by one of the most common cancer-causing changes in cells.

Suspect eliminated as a therapeutic target in B cell lymphoma
Australian researchers have narrowed the focus on which survival proteins are important for the survival of B cell lymphomas, eliminating the protein BCL-W from the 'suspect list'.

Study shows protein inhibitor as potential treatment approach for common mutations found in non-Hodgkin lymphomas
Study shows protein inhibitor as potential treatment approach for common mutations found in non-Hodgkin lymphomas.

Biological mechanism explained: How lymphoma cells metastasize to the brain
Scientists at the German Cancer Research Center have now discovered which molecular mechanism leads to lymphomas forming metastases in the central nervous system.

CNIO participates in a study identifying a novel oncogene for most common types of blood cancer
The study shows that tumour suppressor hnRNP K can lead to cancer.

CD30: From witness to culprit
Cells of certain blood cancers such as Hodgkin's lymphoma carry the protein CD30 on their surface.

Read More: Lymphomas News and Lymphomas Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.