ABSTRACT
Spermidine (SPD) delays age-related pathologies in various organisms. SPD supplementation overcame the impaired immunotherapy against tumors in aged mice by increasing mitochondrial function and activating CD8+ T cells. Treatment of naïve CD8+ T cells with SPD acutely enhanced fatty acid oxidation. SPD conjugated to beads bound to the mitochondrial trifunctional protein (MTP). In the MTP complex, synthesized and purified from Escherichia coli, SPD bound to the α and ß subunits of MTP with strong affinity and allosterically enhanced their enzymatic activities. T cell-specific deletion of the MTP α subunit abolished enhancement of programmed cell death protein 1 (PD-1) blockade immunotherapy by SPD, indicating that MTP is required for SPD-dependent T cell activation.
Subject(s)
CD8-Positive T-Lymphocytes , Mitochondria , Mitochondrial Trifunctional Protein, alpha Subunit , Mitochondrial Trifunctional Protein, beta Subunit , Neoplasms , Spermidine , Animals , Mice , CD8-Positive T-Lymphocytes/immunology , Lymphocyte Activation , Mitochondria/metabolism , Mitochondrial Trifunctional Protein, alpha Subunit/metabolism , Mitochondrial Trifunctional Protein, beta Subunit/metabolism , Spermidine/pharmacology , Spermidine/metabolism , Neoplasms/immunologyABSTRACT
Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1-3. Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8+ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.
Subject(s)
B-Lymphocytes/metabolism , Interleukin-10/immunology , Macrophages/metabolism , Neoplasms/immunology , gamma-Aminobutyric Acid/metabolism , Animals , B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cell Proliferation , Female , Gene Deletion , Glutamate Decarboxylase/deficiency , Glutamate Decarboxylase/genetics , Humans , Inflammation/immunology , Inflammation/prevention & control , Macrophages/immunology , Male , Mice , Neoplasms/pathology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , gamma-Aminobutyric Acid/biosynthesisABSTRACT
Positive selection of high-affinity B cells within germinal centers (GCs) drives affinity maturation of antibody responses. Here, we examined the mechanism underlying the parallel transition from immunoglobulin M (IgM) to IgG. Early GCs contained mostly unswitched IgM+ B cells; IgG+ B cells subsequently increased in frequency, dominating GC responses 14-21 days after antigen challenge. Somatic hypermutation and generation of high-affinity clones occurred with equal efficiency among IgM+ and IgG+ GC B cells, and inactivation of Ig class-switch recombination did not prevent depletion of IgM+ GC B cells. Instead, high-affinity IgG+ GC B cells outcompeted high-affinity IgM+ GC B cells via a selective advantage associated with IgG antigen receptor structure but independent of the extended cytoplasmic tail. Thus, two parallel forms of GC B-cell-positive selection, based on antigen receptor variable and constant regions, respectively, operate in tandem to ensure high-affinity IgG antibodies predominate in mature serum antibody responses.
Subject(s)
B-Lymphocytes/immunology , Germinal Center/immunology , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Animals , Antibody Formation/immunology , Antigens/immunology , Female , Immunoglobulin Class Switching/immunology , Immunoglobulin Variable Region/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Sheep/immunology , Somatic Hypermutation, Immunoglobulin/immunologyABSTRACT
The gut microbiome has garnered attention as an effective target to boost immunity and improve cancer immunotherapy. We found that B cell-defective (BCD) mice, such as µ-membrane targeted deletion (µMT) and activation-induced cytidine deaminase (AID) knockouts (KOs), have elevated antitumor immunity under specific pathogen-free but not germ-free conditions. Microbial dysbiosis in these BCD mice enriched the type I IFN (IFN) signature in mucosal CD8+ T cells, resulting in up-regulation of the type I IFN-inducible protein stem cell antigen-1 (Sca-1). Among CD8+ T cells, naïve cells predominantly circulate from the gut to the periphery, and those that had migrated from the mesenteric lymph nodes (mLNs) to the periphery had significantly higher expression of Sca-1. The gut-educated Sca-1+ naïve subset is endowed with enhanced mitochondrial activity and antitumor effector potential. The heterogeneity and functional versatility of the systemic naïve CD8+ T cell compartment was revealed by single-cell analysis and functional assays of CD8+ T cell subpopulations. These results indicate one of the potential mechanisms through which microbial dysbiosis regulates antitumor immunity.
