Acute impairment of early T cell activation following impediment of mitochondrial electron transport (LB166)

T cells absorb nanometric membrane vesicles, derived from antigen presenting cells, via dual receptor/ligand interactions of T cell receptor (TCR) with cognate peptide/major histocompatibility complex (MHC) complex plus lymphocyte function‐associated antigen 1 (LFA‐1) with intercellular adhesion molecule 1. Our studies have shown that TCR‐mediated signaling is also critically involved in the vesicle absorption, which is likely for the activation of LFA‐1. In an effort to systematically investigate the signaling process involved in the vesicle absorption process, we exploited chemical biology tools and screened chemical libraries to identify small molecules to interfere with the absorption process. Interestingly, it was found in the course of the study that brief treatments (1 hour) with various mitochondrial antagonists, including complex I, II, III, IV and V inhibitors,, resulted in ubiquitous inhibition of the vesicle absorption at concentrations not compromising viability of T cells. Further studies revealed that the mitochondrial drug treatments caused impairment of specific membrane‐proximal TCR signaling event(s). Thus, the activation of Akt and PLC‐γ1 and entry of extracellular Ca2+ following TCR triggering were severely compromised, while polymerization of monomeric actins immediately monitored upon triggering of TCRs appeared to progress normally even after the treatments. Dynamic F‐actin rearrangement concurring with the vesicle absorption was, however, also found to be impeded by the drug treatments, implying that the inhibition by the drug treatments of downstream signaling events at least in part resulted from the impairment of directional relocation of signaling and cell surface molecules accompanying with actin rearrangement. Grant Funding Source : Supported by Chungnam National University Grant (2013‐1892)