Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model.
Gamma-aminobutyric acid (GABA) is both a major inhibitory neurotransmitter in the CNS and a product of beta cells of the peripheral islets. Our previous studies, and those of others, have shown that T cells express functional GABAA receptors. However, their subunit composition and physiological relevance are unknown. In this study, we show that a subset of GABAA receptor subunits are expressed by CD4+ 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 Ags ex vivo, and administration of GABA retarded the adoptive transfer of type 1 diabetes (T1D) in NOD/scid mice. Furthermore, treatment with low dose of GABA (600 microg daily) dramatically inhibited the development of proinflammatory T cell responses and disease progression in T1D-prone NOD mice that already had established autoimmunity. Finally, GABA inhibited TCR-mediated T cell cycle progression in vitro, which may underlie GABA's therapeutic effects. The immunoinhibitory effects of GABA on T cells may contribute to the long prodomal period preceding the development of T1D, the immunological privilege of the CNS, and the regulatory effects of alcohol on immune responses. Potentially, pharmacological modulation of GABAA receptors on T cells may provide a new class of therapies for human T1D as well as other inflammatory diseases.
Tian
Jide
J
Department of Molecular and Medical Pharmacology, University of California, Los Angeles 90095, USA. jtian@mednet.ucla.edu
Lu
Yuxin
Y
Zhang
Hanwei
H
Chau
Cindy H
CH
Dang
Hoa N
HN
Kaufman
Daniel L
DL
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry; D002453:Cell Cycle / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D007249:Inflammation / Q000517:prevention & control*; D051379:Mice; D016688:Mice, Inbred NOD; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000032:analysis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D021122:Protein Subunits; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid