Acute inhibition of selected membrane-proximal mouse T cell receptor signaling by mitochondrial antagonists

• Published in: PloS one Vol. 4; no. 11; p. e7738
• Main Authors: Kim, Kwangmi, Wang, Lin, Hwang, Inkyu
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10-11-2009; Public Library of Science (PLoS)
• Subjects: Absorption; Actin; Actins - metabolism; Activation; AKT protein; Animals; Antigen-presenting cells; Antigens; Calcium (extracellular); Calcium - metabolism; Cell adhesion; Cell Biology/Cell Adhesion; Cell Biology/Cell Signaling; Cell Biology/Chemical Biology of the Cell; Cell Biology/Cytoskeleton; Cell Biology/Leukocyte Signaling and Gene Expression; Cell Cycle; Cell Membrane - metabolism; Cell Proliferation; Cell surface; Diabetes mellitus; Diabetes therapy; Downstream effects; Drugs; Environmental effects; Environmental factors; High-throughput screening; Hypoglycemic agents; Immunity; Immunology/Immunomodulation; Immunology/Leukocyte Activation; Immunomodulation; Immunosuppressive agents; Immunotherapy; Inhibition; Intercellular adhesion molecule 1; Kinases; LFA-1 antigen; Lymphocytes; Lymphocytes T; Major Histocompatibility Complex; Membrane vesicles; Membranes; Metformin; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Modulators; Muscle proteins; Phospholipase C gamma - metabolism; Phosphorylation; Polymerization; Receptors, Antigen, T-Cell - metabolism; Regulatory mechanisms (biology); Relocation; Rodents; Signal Transduction; Signaling; T cell receptors; T cells; T-cell receptor; T-Lymphocytes - immunology; Viability; La Jolla California; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0007738

T cells absorb nanometric membrane vesicles, prepared from plasma membrane of antigen presenting cells, via dual receptor/ligand interactions of T cell receptor (TCR) with cognate peptide/major histocompatibility complex (MHC) plus lymphocyte function-associated antigen 1 (LFA-1) with intercellular adhesion molecule 1. TCR-mediated signaling for LFA-1 activation is also required for the vesicle absorption. Exploiting those findings, we had established a high throughput screening (HTS) platform and screened a library for isolation of small molecules inhibiting the vesicle absorption. Follow-up studies confirmed that treatments (1 hour) with various mitochondrial antagonists, including a class of anti-diabetic drugs (i.e., Metformin and Phenformin), resulted in ubiquitous inhibition of the vesicle absorption without compromising viability of T cells. Further studies revealed that the mitochondrial drug treatments caused impairment of specific membrane-proximal TCR signaling event(s). Thus, activation of Akt and PLC-gamma1 and entry of extracellular Ca(2+) following TCR stimulation were attenuated while polymerization of monomeric actins upon TCR triggering progressed normally after the treatments. Dynamic F-actin rearrangement concurring with the vesicle absorption was also found to be impaired by the drug treatments, implying that the inhibition by the drug treatments of downstream signaling events (and the vesicle absorption) could result from lack of directional relocation of signaling and cell surface molecules. We also assessed the potential application of mitochondrial antagonists as immune modulators by probing effects of the long-term drug treatments (24 hours) on viability of resting primary T cells and cell cycle progression of antigen-stimulated T cells. This study unveils a novel regulatory mechanism for T cell immunity in response to environmental factors having effects on mitochondrial function.