{"id":"ec2a166a-c0cb-50bb-a22b-b33ae02d476c","stable_key":"1b599eb7-b22a-5fda-bcf0-9d92b5ae1311:gb-gaba-slows-the-autoimmune-t-cell","predicate":"inhibits","statement":"A subset of GABA-A receptor subunits are expressed by CD4-positive T cells including the delta subunit that confers high affinity for GABA and sensitivity to alcohol, GABA at relatively low concentrations down-regulated effector T cell responses to beta cell antigens ex vivo and administration of GABA retarded the adoptive transfer of type 1 diabetes in NOD/scid mice, treatment with a low dose of GABA at 600 micrograms daily dramatically inhibited the development of proinflammatory T cell responses and disease progression in disease-prone mice that already had established autoimmunity, and GABA inhibited T cell receptor-mediated T cell cycle progression in vitro which may underlie the therapeutic effects.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"6fc1f7ed-ee29-5f59-92b2-7aa436e081b4","mechanism_event_label":"Low doses slowed the immune attack on the insulin-producing cells even after that attack had already started.","subject":{"id":"d5b98fa8-0612-5a5a-aa3c-6cfd8ff88867","slug":"gaba","display_name":"Gamma-aminobutyric acid","entity_type_key":"small_molecule"},"object":{"id":"64e9f845-04c2-54c5-bdaa-14eda8260c4a","slug":"type-1-diabetes","display_name":"Type 1 diabetes","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"6fc1f7ed-ee29-5f59-92b2-7aa436e081b4","stable_key":"1b599eb7-b22a-5fda-bcf0-9d92b5ae1311:gb-gaba-slows-the-autoimmune-t-cell-event","event_type":"biochemical_relationship","label":"Low doses slowed the immune attack on the insulin-producing cells even after that attack had already started.","description":"A subset of GABA-A receptor subunits are expressed by CD4-positive T cells including the delta subunit that confers high affinity for GABA and sensitivity to alcohol, GABA at relatively low concentrations down-regulated effector T cell responses to beta cell antigens ex vivo and administration of GABA retarded the adoptive transfer of type 1 diabetes in NOD/scid mice, treatment with a low dose of GABA at 600 micrograms daily dramatically inhibited the development of proinflammatory T cell responses and disease progression in disease-prone mice that already had established autoimmunity, and GABA inhibited T cell receptor-mediated T cell cycle progression in vitro which may underlie the therapeutic effects.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"11faeac7-c2f1-5c50-9142-ee665604c6cc","slug":"cd4-t-cell","display_name":"CD4 T cell","entity_type_key":"cell_type"},"role":"suppressed_cell","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"e6aa2b28-0c94-574c-827c-8987b31523fb","slug":"gabrd","display_name":"GABA-A receptor delta subunit / GABRD","entity_type_key":"protein"},"role":"high_affinity_subunit","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"772ee1ec-23a8-513e-97d3-4b7963177307","slug":"t-cell-proliferation","display_name":"T-cell proliferation, model specified","entity_type_key":"cellular_process"},"role":"inhibited_process","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"66709f33-8eeb-5618-b262-023a13db02ad","slug":"islet-beta-cell","display_name":"Pancreatic islet beta cell","entity_type_key":"cell_type"},"role":"protected_cell","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"d5b98fa8-0612-5a5a-aa3c-6cfd8ff88867","slug":"gaba","display_name":"Gamma-aminobutyric acid","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"64e9f845-04c2-54c5-bdaa-14eda8260c4a","slug":"type-1-diabetes","display_name":"Type 1 diabetes","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/gaba-research/15470076.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"e5523c02fc4571d5ab6c23776794b4b5cf025fb86cdba9acdc12011f3a6b2e09\", \"start_char\": 0, \"end_char\": 1443, \"text_sha256\": \"e5523c02fc4571d5ab6c23776794b4b5cf025fb86cdba9acdc12011f3a6b2e09\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Subunit analysis with ex vivo antigen responses, adoptive transfer and treatment of disease-prone mice","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"GABA at low concentrations ex vivo, and 600 micrograms daily in mice with established autoimmunity","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A mouse type 1 diabetes model. The cell cycle result offers a mechanism for the disease effect but is measured separately from it.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"GABA research collection; topical membership is not evidence of a direct clinical effect, and the sign of a GABA response depends on the chloride gradient of the cell it was measured in.","comparator":null,"unit":null,"notes":"","entity":{"slug":"gaba","display_name":"Gamma-aminobutyric acid","entity_type_key":"small_molecule"}},{"dimension":"organism","value_text":"Mouse","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Low doses slowed the immune attack on the insulin-producing cells even after that attack had already started.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[gb-p15470076] Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model. (2004). https://pubmed.ncbi.nlm.nih.gov/15470076/ DOI: 10.4049/jimmunol.173.8.5298","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"CD4 T cell and pancreatic islet","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"e6f3373b-dcc7-57d7-8626-70fb19e9920f","evidence_kind":"source_excerpt","locator":"Lines 534-545","start_line":534,"end_line":545,"excerpt":"### gb-gaba-slows-the-autoimmune-t-cell\nA subset of GABA-A receptor subunits are expressed by CD4-positive T cells including the delta subunit that confers high affinity for GABA and sensitivity to alcohol, GABA at relatively low concentrations down-regulated effector T cell responses to beta cell antigens ex vivo and administration of GABA retarded the adoptive transfer of type 1 diabetes in NOD/scid mice, treatment with a low dose of GABA at 600 micrograms daily dramatically inhibited the development of proinflammatory T cell responses and disease progression in disease-prone mice that already had established autoimmunity, and GABA inhibited T cell receptor-mediated T cell cycle progression in vitro which may underlie the therapeutic effects.\nCondition category: normal\nnutrient_topic: GABA research collection; topical membership is not evidence of a direct clinical effect, and the sign of a GABA response depends on the chloride gradient of the cell it was measured in.\nplain_language: Low doses slowed the immune attack on the insulin-producing cells even after that attack had already started.\norganism: Mouse\ntissue_or_cell_type: CD4 T cell and pancreatic islet\nexperimental_model: Subunit analysis with ex vivo antigen responses, adoptive transfer and treatment of disease-prone mice\nlimitations: A mouse type 1 diabetes model. The cell cycle result offers a mechanism for the disease effect but is measured separately from it.\nexposure: GABA at low concentrations ex vivo, and 600 micrograms daily in mice with established autoimmunity\nevidence_span: {\"source_cache\": \"artifacts/gaba-research/15470076.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"e5523c02fc4571d5ab6c23776794b4b5cf025fb86cdba9acdc12011f3a6b2e09\", \"start_char\": 0, \"end_char\": 1443, \"text_sha256\": \"e5523c02fc4571d5ab6c23776794b4b5cf025fb86cdba9acdc12011f3a6b2e09\"}\n[gb-p15470076] Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model. (2004). https://pubmed.ncbi.nlm.nih.gov/15470076/ DOI: 10.4049/jimmunol.173.8.5298","model_system":"Subunit analysis with ex vivo antigen responses, adoptive transfer and treatment of disease-prone mice","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [gb-p15470076] Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model. (2004). https://pubmed.ncbi.nlm.nih.gov/15470076/ DOI: 10.4049/jimmunol.173.8.5298","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"197c25bb-45fa-5e97-b3ab-2d2eff4e0d0a","stable_key":"import-1b599eb7-b22a-5fda-bcf0-9d92b5ae1311","title":"GABA: a ligand with no sign of its own, the cofactor that limits its synthesis, the barrier that keeps it out of the brain, and the immune settings where the same molecule protects and harms (2026-09-22)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"07e36027ff70dbbe5563cddfa4758fd9b9b6eec148faecccafd476900b770456","revision_id":"a12d61de-f189-5bda-af3d-f31a1e61bccf","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"dcad2bb0-ed40-520b-9dc8-d0a35b9f3c93","title":"Is GABA protective or harmful when the immune system is involved?","kind":"qualification","status":"open","why":"The direction reverses with the setting, and every record here is consistent within its own. In autoimmunity it protects: low concentrations slow effector T cell responses and disease progression in a mouse type 1 diabetes model, and raising GABAergic activity improves ongoing paralysis in an autoimmune model of central nervous system disease by acting on antigen-presenting cells. In intracellular bacterial infection it also protects, but by the opposite kind of action: infection lowers GABA, and giving it drives autophagy and phagosomal maturation so that blocking GABAergic signalling increases bacterial load in two species. In tumours it harms: B cell-derived GABA turns monocytes into interleukin-10-secreting macrophages that shut down CD8 killing, and deleting the enzyme that makes it in B cells improves anti-tumour responses. A macrophage record cuts across all three, since removing the transporter that carries GABA into the cell lowered interleukin-1 beta, which makes GABA uptake pro-inflammatory in that setting rather than anti-inflammatory. What the collection does not contain is any measurement that would let these be reduced to one mechanism with a context-dependent sign.","resolution":"Unresolved and possibly not one question. The records differ in cell, challenge and readout simultaneously, and are recorded side by side rather than reconciled.","created_at":"2026-09-23 01:18:27","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/dcad2bb0-ed40-520b-9dc8-d0a35b9f3c93","sides":[{"conflict_id":"dcad2bb0-ed40-520b-9dc8-d0a35b9f3c93","ordinal":0,"label":"Low doses slowed the immune attack on the insulin-producing cells even after that attack had already started.","revision_id":"a12d61de-f189-5bda-af3d-f31a1e61bccf","start_line":534,"end_line":545,"quote":"### gb-gaba-slows-the-autoimmune-t-cell\nA subset of GABA-A receptor subunits are expressed by CD4-positive T cells including the delta subunit that confers high affinity for GABA and sensitivity to alcohol, GABA at relatively low concentrations down-regulated effector T cell responses to beta cell antigens ex vivo and administration of GABA retarded the adoptive transfer of type 1 diabetes in NOD/scid mice, treatment with a low dose of GABA at 600 micrograms daily dramatically inhibited the development of proinflammatory T cell responses and disease progression in disease-prone mice that already had established autoimmunity, and GABA inhibited T cell receptor-mediated T cell cycle progression in vitro which may underlie the therapeutic effects.\nCondition category: normal\nnutrient_topic: GABA research collection; topical membership is not evidence of a direct clinical effect, and the sign of a GABA response depends on the chloride gradient of the cell it was measured in.\nplain_language: Low doses slowed the immune attack on the insulin-producing cells even after that attack had already started.\norganism: Mouse\ntissue_or_cell_type: CD4 T cell and pancreatic islet\nexperimental_model: Subunit analysis with ex vivo antigen responses, adoptive transfer and treatment of disease-prone mice\nlimitations: A mouse type 1 diabetes model. The cell cycle result offers a mechanism for the disease effect but is measured separately from it.\nexposure: GABA at low concentrations ex vivo, and 600 micrograms daily in mice with established autoimmunity\nevidence_span: {\"source_cache\": \"artifacts/gaba-research/15470076.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"e5523c02fc4571d5ab6c23776794b4b5cf025fb86cdba9acdc12011f3a6b2e09\", \"start_char\": 0, \"end_char\": 1443, \"text_sha256\": \"e5523c02fc4571d5ab6c23776794b4b5cf025fb86cdba9acdc12011f3a6b2e09\"}\n[gb-p15470076] Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model. (2004). https://pubmed.ncbi.nlm.nih.gov/15470076/ DOI: 10.4049/jimmunol.173.8.5298","source_key":"import-1b599eb7-b22a-5fda-bcf0-9d92b5ae1311","source_title":"GABA: a ligand with no sign of its own, the cofactor that limits its synthesis, the barrier that keeps it out of the brain, and the immune settings where the same molecule protects and harms (2026-09-22)","claim_ids":["ec2a166a-c0cb-50bb-a22b-b33ae02d476c"]},{"conflict_id":"dcad2bb0-ed40-520b-9dc8-d0a35b9f3c93","ordinal":1,"label":"Here the same molecule helps rather than suppresses: it drives the cell to digest the bacteria inside it, and blocking it lets the infection grow.","revision_id":"a12d61de-f189-5bda-af3d-f31a1e61bccf","start_line":586,"end_line":597,"quote":"### gb-gaba-helps-the-host-kill-bacteria\nIntracellular bacterial infection decreases GABA levels in vitro in macrophages and in vivo in sera, treatment of macrophages with GABA or GABAergic drugs promotes autophagy activation, enhances phagosomal maturation and antimicrobial responses against mycobacterial infection, in macrophages the GABAergic defense is mediated via macrophage type A GABA receptor, intracellular calcium release and the GABA type A receptor-associated protein-like 1, and GABAergic inhibition increases bacterial loads in mice and zebrafish in vivo suggesting that the GABAergic defense plays an essential function in metazoan host defenses.\nCondition category: normal\nnutrient_topic: GABA research collection; topical membership is not evidence of a direct clinical effect, and the sign of a GABA response depends on the chloride gradient of the cell it was measured in.\nplain_language: Here the same molecule helps rather than suppresses: it drives the cell to digest the bacteria inside it, and blocking it lets the infection grow.\norganism: Mouse and zebrafish\ntissue_or_cell_type: Macrophage\nexperimental_model: Autophagy and phagosome assays in macrophages with receptor and protein dependency, and infection burden in two whole animals\nlimitations: The dependency on the receptor and on a specific autophagy protein is tested, and the outcome is measured in two species. The direction is the opposite of the autoimmunity records.\nexposure: GABA and GABAergic drugs during intracellular mycobacterial infection, with GABAergic inhibition in vivo\nevidence_span: {\"source_cache\": \"artifacts/gaba-research/30305619.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"4d53b15743f61b910fb1db4781905673c81a070c12245068a369548544e3bc6e\", \"start_char\": 0, \"end_char\": 1146, \"text_sha256\": \"4d53b15743f61b910fb1db4781905673c81a070c12245068a369548544e3bc6e\"}\n[gb-p30305619] GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections. (2018). https://pubmed.ncbi.nlm.nih.gov/30305619/ DOI: 10.1038/s41467-018-06487-5","source_key":"import-1b599eb7-b22a-5fda-bcf0-9d92b5ae1311","source_title":"GABA: a ligand with no sign of its own, the cofactor that limits its synthesis, the barrier that keeps it out of the brain, and the immune settings where the same molecule protects and harms (2026-09-22)","claim_ids":["31793702-4977-5119-b886-ea23ba6e7e5f"]},{"conflict_id":"dcad2bb0-ed40-520b-9dc8-d0a35b9f3c93","ordinal":2,"label":"B cells release this molecule into a tumour, where it turns arriving monocytes into cells that shut down the killers.","revision_id":"a12d61de-f189-5bda-af3d-f31a1e61bccf","start_line":599,"end_line":610,"quote":"### gb-b-cells-secrete-gaba-that-shields-tumours\nWe identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells, B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8-positive T cell killer function, and in mice B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses.\nCondition category: normal\nnutrient_topic: GABA research collection; topical membership is not evidence of a direct clinical effect, and the sign of a GABA response depends on the chloride gradient of the cell it was measured in.\nplain_language: B cells release this molecule into a tumour, where it turns arriving monocytes into cells that shut down the killers.\norganism: Mouse\ntissue_or_cell_type: B cell, monocyte and tumour\nexperimental_model: Identification of a metabolite secreted by activated B cells, with monocyte differentiation and two genetic tests in mice\nlimitations: The B cell-specific enzyme deletion is what makes the source assignment strong. The enzyme deleted is GAD67, not the GAD65 that is the diabetes autoantigen.\nexposure: B cell-derived GABA, with B cell deficiency and B cell-specific inactivation of the GABA-generating enzyme GAD67\nevidence_span: {\"source_cache\": \"artifacts/gaba-research/34732892.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"907d2a95afcac30a55ebfa4a6056c31ca53c452caff350ded70a60c9fc2eb17b\", \"start_char\": 0, \"end_char\": 878, \"text_sha256\": \"907d2a95afcac30a55ebfa4a6056c31ca53c452caff350ded70a60c9fc2eb17b\"}\n[gb-p34732892] B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity. (2021). https://pubmed.ncbi.nlm.nih.gov/34732892/ DOI: 10.1038/s41586-021-04082-1","source_key":"import-1b599eb7-b22a-5fda-bcf0-9d92b5ae1311","source_title":"GABA: a ligand with no sign of its own, the cofactor that limits its synthesis, the barrier that keeps it out of the brain, and the immune settings where the same molecule protects and harms (2026-09-22)","claim_ids":["69312f99-ae5f-59d6-89ff-adc910fda9b4"]},{"conflict_id":"dcad2bb0-ed40-520b-9dc8-d0a35b9f3c93","ordinal":3,"label":"Taking away the carrier that moves GABA into the macrophage lowered its main inflammatory output, through a metabolic route and not an electrical one.","revision_id":"a12d61de-f189-5bda-af3d-f31a1e61bccf","start_line":560,"end_line":571,"quote":"### gb-the-transporter-sustains-il1b\nGABA transporter GAT2 modulates macrophage function and GAT2 deficiency lowers the production of interleukin-1 beta in proinflammatory macrophages, mechanistically GAT2 deficiency boosts the betaine, S-adenosylmethionine and hypoxanthine metabolic pathway to inhibit transcription factor KID3 expression through increased DNA methylation in its promoter region, KID3 regulates oxidative phosphorylation via targeting the expression of related genes and is also critical for NLRP3-ASC-caspase-1 complex formation, and GAT2 deficiency attenuates macrophage-mediated inflammatory responses in vivo including lipopolysaccharide-induced sepsis, infection-induced pneumonia and high-fat diet-induced obesity.\nCondition category: normal\nnutrient_topic: GABA research collection; topical membership is not evidence of a direct clinical effect, and the sign of a GABA response depends on the chloride gradient of the cell it was measured in.\nplain_language: Taking away the carrier that moves GABA into the macrophage lowered its main inflammatory output, through a metabolic route and not an electrical one.\norganism: Mouse\ntissue_or_cell_type: Proinflammatory macrophage\nexperimental_model: Transporter deficiency with metabolic pathway analysis, promoter methylation and three in vivo inflammatory models\nlimitations: The mechanism assigned here is metabolic and transcriptional, running through methylation of a transcription factor promoter, rather than an electrophysiological one.\nexposure: GAT2 deficiency in macrophages, with lipopolysaccharide sepsis, infection-induced pneumonia and high-fat diet models\nevidence_span: {\"source_cache\": \"artifacts/gaba-research/33827820.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"7c654d761170222f117b179e232f555803d6a7cadcfb2eed7b95c45539787cff\", \"start_char\": 0, \"end_char\": 1140, \"text_sha256\": \"7c654d761170222f117b179e232f555803d6a7cadcfb2eed7b95c45539787cff\"}\n[gb-p33827820] GABA transporter sustains IL-1β production in macrophages. (2021). https://pubmed.ncbi.nlm.nih.gov/33827820/ DOI: 10.1126/sciadv.abe9274","source_key":"import-1b599eb7-b22a-5fda-bcf0-9d92b5ae1311","source_title":"GABA: a ligand with no sign of its own, the cofactor that limits its synthesis, the barrier that keeps it out of the brain, and the immune settings where the same molecule protects and harms (2026-09-22)","claim_ids":["7e56eb79-e42e-5719-bc6e-39be78b07f89"]}]}],"corrections":[],"research":null}