The brain and its borders create a highly dynamic microenvironment populated with immune cells. Yet characterization of immune cells within the naive brain compartment remains limited. In this study, we used CyTOF mass cytometry to characterize the immune populations of the naive mouse brain using 44 cell surface markers. By comparing immune cell composition and cell profiles between the brain compartment and blood, we were able to characterize previously undescribed cell subsets of CD8 T cells, B cells, NK cells and dendritic cells in the naive brain. Using flow cytometry, we show differential distributions of immune populations between meninges, choroid plexus and parenchyma. We demonstrate the phenotypic ranges of resident myeloid cells and identify CD44 as a marker for infiltrating immune populations. This study provides an approach for a system-wide view of immune populations in the brain and is expected to serve as a resource for understanding brain immunity.

Positive expectations contribute to the clinical benefits of the placebo effect. Such positive expectations are mediated by the brain's reward system; however, it remains unknown whether and how reward system activation affects the body's physiology and, specifically, immunity. Here we show that activation of the ventral tegmental area (VTA), a key component of the reward system, strengthens immunological host defense. We used 'designer receptors exclusively activated by designer drugs' (DREADDs) to directly activate dopaminergic neurons in the mouse VTA and characterized the subsequent immune response after exposure to bacteria (Escherichia coli), using time-of-flight mass cytometry (CyTOF) and functional assays. We found an increase in innate and adaptive immune responses that were manifested by enhanced antibacterial activity of monocytes and macrophages, reduced in vivo bacterial load and a heightened T cell response in the mouse model of delayed-type hypersensitivity. By chemically ablating the sympathetic nervous system (SNS), we showed that the reward system's effects on immunity are, at least partly, mediated by the SNS. Thus, our findings establish a causal relationship between the activity of the VTA and the immune response to bacterial infection.

No abstract

Regulating immunity is a leading target for cancer therapy. Here, we show that the anti-tumor immune response can be modulated by the brain’s reward system, a key circuitry in emotional processes. Activation of the reward system in tumor-bearing mice (Lewis lung carcinoma (LLC) and B16 melanoma) using chemogenetics (DREADDs), resulted in reduced tumor weight. This effect was mediated via the sympathetic nervous system (SNS), manifested by an attenuated noradrenergic input to a major immunological site, the bone marrow. Myeloid derived suppressor cells (MDSCs), which develop in the bone marrow, became less immunosuppressive following reward system activation. By depleting or adoptively transferring the MDSCs, we demonstrated that these cells are both necessary and sufficient to mediate reward system effects on tumor growth. Given the central role of the reward system in positive emotions, these findings introduce a physiological mechanism whereby the patient’s psychological state can impact anti-tumor immunity and cancer progression.

In the originally published version of this article, we reported that neurons in the insular cortex encode and retrieve specific immune responses. We have identified minor errors in the STAR Methods section, which are located in the paragraph entitled ''Activitydependent cell labeling.'' First, the amount of Tamoxifen injected into the mice should be 150 mg/kg instead of 15 mg/kg as we originally stated. Second, the injected dose of the 4-OHT final solution is missing from the text; it should be 50 mg/kg. We have also corrected errors in the reporting of the n values for experiments in the figure legends (Figures 2C, 2D, 2P, 3F, and 3H) and the y-axis description for Figure S5M.

Highlights d Optogenetic activation of local sympathetic fibers in the colon attenuates colitis d The local sympathetic activation reduces immune cell abundance d Reduction in immune abundance is mediated by a decrease in endothelial MAdCAM-1

Polyclonal activation of developing B cells is an injurious process, because most of these cells are nontolerant and express autoreactive receptors. CpG DNA is a polyclonal activator of mature B cells, but its effect on developing B cells is unclear. We tested whether developing, nontolerant B cells are responsive to mitogenic stimulation by CpG DNA and whether such a stimulus can interfere with the establishment of central tolerance. We found that developing B cells express Toll-like receptor 9 and undergo a polyclonal response to CpG DNA stimulation, as revealed by proliferation and differentiation to antibody-producing cells. In vitro and ex vivo experiments revealed that stimulation with CpG DNA protects immature B cells from negative selection imposed by apoptosis and receptor editing and results in the production of autoantibodies. Finally, we found that in vivo administration of CpG DNA activates immature B cells in the bone marrow and suppresses the expression of recombinationactivating genes in a mouse model of central tolerance and receptor editing. These results suggest that mitogenic signals provided by CpG DNA stimulate nontolerant immature B cells in the bone marrow and have the potential to interfere with central tolerance.

TOLL-like receptor (TLR) ligands stimulate class switch recombination (CSR) in mature B cells. We showed earlier that developing B cells in the bone marrow (BM) express TLR9 and are responsive to CpG DNA. Since CSR is a critical process for synthesis of effector antibodies, we studied the competence of precursor B cells to undergo CSR in response to TLR ligands, and the regulation of these cells. We found that CSR is induced throughout B lymphopoiesis in response to CpG and to LPS. However, sequencing analysis revealed aberrant joining of the switch junctions. In addition, we found that this CSR is independent of IgM expression and/or VDJ assembly and is directed to a specific isotype by cytokines. Finally, we found that activation of the switched precursor B cells is regulated by Fas. Thus, BM B cells can be activated by TLR ligands to undergo CSR and to secrete non-IgM antibodies. However, the effector potential of these cells is regulated by the Fas pathway.