21 research outputs found
Tonic TCR Signaling Inversely Regulates the Basal Metabolism of CD4
The contribution of self-peptide-MHC signaling in CD
The Study of High-Affinity TCRs Reveals Duality in T Cell Recognition of Antigen: Specificity and Degeneracy
Loss of NavĪ²4-Mediated Regulation of Sodium Currents in Adult Purkinje Neurons Disrupts Firing and Impairs Motor Coordination and Balance
Summary: The resurgent component of voltage-gated Na+ (Nav) currents, INaR, has been suggested to provide the depolarizing drive for high-frequency firing and to be generated by voltage-dependent Nav channel block (at depolarized potentials) and unblock (at hyperpolarized potentials) by the accessory NavĪ²4 subunit. To test these hypotheses, we examined the effects of the targeted deletion of Scn4b (NavĪ²4) on INaR and on repetitive firing in cerebellar Purkinje neurons. We show here that Scn4bā/ā animals have deficits in motor coordination and balance and that firing rates in Scn4bā/ā Purkinje neurons are markedly attenuated. Acute, inĀ vivo short hairpin RNA (shRNA)-mediated āknockdownā of NavĪ²4 in adult Purkinje neurons also reduced spontaneous and evoked firing rates. Dynamic clamp-mediated addition of INaR partially rescued firing in Scn4bā/ā Purkinje neurons. Voltage-clamp experiments revealed that INaR was reduced (by ā¼50%), but not eliminated, in Scn4bā/ā Purkinje neurons, revealing that additional mechanisms contribute to generation of INaR. : Loss of NavĪ²4 attenuates, but does not eliminate, the resurgent sodium current (INaR) in cerebellar Purkinje neurons, revealing that additional mechanism(s) contribute to the generation of INaR. Ransdell etĀ al. also find that INaR magnitude tunes the firing rate of Purkinje neurons and that NavĪ²4ā/ā animals display balance and motor deficits. Keywords: cerebellum, resurgent sodium current, Scn4bā/ā, Scn4b-targeted shRNA, dynamic clam
Polysaccharide Capsules Equip the Human Symbiont Bacteroides thetaiotaomicron to Modulate Immune Responses to a Dominant Antigen in the Intestine
Bacteria express multiple diverse capsular polysaccharides (CPSs) for protection against environmental and host factors, including the host immune system. Using a mouse TCR transgenic CD4+ T cell, BĪøOM, that is specific for B. thetaiotaomicron and a complete set of single CPS-expressing B. thetaiotaomicron strains, we ask whether CPSs can modify the immune responses to specific bacterial Ags. Acapsular B. thetaiotaomicron, which lacks all B. thetaiotaomicron CPSs, stimulated BĪøOM T cells more strongly than wild-type B. thetaiotaomicron Despite similar levels of BĪøOM Ag expression, many single CPS-expressing B. thetaiotaomicron strains were antistimulatory and weakly activated BĪøOM T cells, but a few strains were prostimulatory and strongly activated BĪøOM T cells just as well or better than an acapsular strain. B. thetaiotaomicron strains that expressed an antistimulatory CPS blocked Ag delivery to the immune system, which could be rescued by Fc receptor-dependent Ab opsonization. All single CPS-expressing B. thetaiotaomicron strains stimulated the innate immune system to skew toward M1 macrophages and release inflammatory cytokines in an MyD88-dependent manner, with antistimulatory CPS activating the innate immune system in a weaker manner than prostimulatory CPS. The expression of antistimulatory versus prostimulatory CPSs on outer membrane vesicles also regulated immune responses. Moreover, antistimulatory and prostimulatory single CPS-expressing B. thetaiotaomicron strains regulated the activation of Ag-specific and polyclonal T cells as well as clearance of dominant Ag in vivo. These studies establish that the immune responses to specific bacterial Ags can be modulated by a diverse set of CPSs