GABA released by B-cells blunts the immune response to tumors

by  RIKEN

Fig. 1: Metabolic remodeling of immunized LNs and B cell-dependent GABA production. a–e, Mice were injected in the foot pad with OVA + CFA, and iLNs and cLNs were collected for metabolite MS and histology at day 7: WT (n = 11), Cd3–/– (n = 5), muMt–/– (n = 4) and Rag1–/– (n = 3). a, Immunohistochemistry of B cells (B220), T cells (CD3) and myeloid cells (CD11c). Scale bars, 200 µm. b, Principal-component analysis of metabolites in iLNs and cLNs. PC, principal component. c, Pathway analysis of metabolites with significantly different abundance between iLNs and cLNs in WT mice (two-tailed unpaired t-test, P < 0.05). d, Relative Cd3–/– (B cell signature) and muMt–/– (T cell signature) iLN metabolites, showing only metabolites that also differed between iLNs and cLNs in WT mice. e, GABA levels in the indicated cLNs or iLNs, relative to WT cLNs (data are shown as mean ± s.e.m.; two-tailed unpaired t-test: ***P < 0.001, ****P < 0.0001; NS, not significant). f, Correlation of plasma GABA levels with disease activity scores (Simplified Disease Activity Index (SDAI) or Activity Score 28 using C-reactive protein (DAS28-CRP)) and plasma anti-cyclic citrullinated peptide (CCP) antibody levels in patients with rheumatoid arthritis (n = 138). Pearson’s and Spearman’s r and P values (two tailed) are shown. n indicates the number of biological replicates. Data are representative of two experiments (a–e). Exact P values are provided in the Source Data. Credit: DOI: 10.1038/s41586-021-04082-1

A group of scientists led by researchers from the RIKEN Center for Integrative Medical Sciences have discovered that B-cells, a type of immune cell, secrete the neurotransmitter GABA, and also found that the GABA secreted by the B-cells promoted the emergence of anti-inflammatory macrophages, blunting the body’s cytotoxic T-cell-based response to tumors. According to the authors, this work, published in Nature, could lead to the development of therapies that work to fine tune the immune response.

The research project involved looking at small metabolites in lymph nodes, where immune cells aggregate. First, the researchers stimulated an immune response in mice by injecting them with ovalbumin, and then looked at activated lymph nodes on the same side of the body as the injection, compared to lymph nodes on the other side that had not been activated, to determine the effect of the response on small metabolites. A surprising finding of the initial research was the discovery of a high amount of GABA, a metabolite which is used in the brain as a neurotransmitter that can help calm feelings such as anxiety, stress and fear, in the activated nodes compared to the non-activated ones.

Further work, which involved comparing mice that were deficient in T-cells or B-cells or neither, determined that the GABA was being released by immune B-cells, an unexpected finding.

“Naturally,” says first author Baihao Zhang, a postdoctoral researcher at the RIKEN Center for Integrative Medical Sciences, “we wanted to examine the significance of this release of GABA.” Through further experiments, they found that in B-cell deficient mice that had tumors, implanting a pellet that released GABA led to faster tumor growth, implying that the GABA was having a negative effect on tumor control. Indeed, they found that the GABA led to a decrease in cytotoxic T-cells, which are important players in fighting tumors, and that drugs that block GABA, which are currently used in psychiatric medicine, prevented this. In addition, they found that GABA stimulated the differentiation of monocytes into anti-inflammatory macrophages, which are known to blunt T-cell reaction to tumors. “The implication,” he continues,” is that the GABA caused the increase in anti-inflammatory macrophages, leading to a reduction in the activity of the cytotoxic T-cells.”

According to Zhang, “It was very surprising to find that immune cells regulate each other through such small soluble metabolites produced by themselves.”

According to Sidonia Fagarasan, the leader of the research group, “GABA was known to be produced in plants in response to environmental stress. Also, GABA is produced by bacteria in the gut. We are very happy to have demonstrated that immune cells, particularly B cells secrete the neurotransmitter GABA, highlighting this metabolite’s position at the intersection between neurology, immunology, symbiology and physiology. We found that as in the brain where GABA can inhibit nerve signals, B cell-derived GABA has an immunoregulatory function. In some cases, this inhibition can be harmful. In particular, we showed that GABA made by B-cells limited immune responses to cancer. In other cases, such as autoimmune inflammatory responses or virus-triggered inflammation, GABA’s inhibitory effect could be beneficial.”

Looking to the future, she continues, “There is still much to learn and biology continues to astonish us. We are trying to understand the molecular mechanism through which GABA modulates monocyte differentiation, with the aim to develop or improve immunotherapy for infections, autoimmune diseases, and cancers. Drugs that are currently being used to inhibit GABA signaling for the treatment of neurological diseases such as epilepsy, for example, might be repurposed to enhance the ability of the immune system to fight certain types of cancer.”