Title: TLR agonists downregulate H2-O in CD8α- dendritic cells

Presenter: Dr. Gavin Porter

University: The University of Hong Kong

Time: 15:00-16:30, 21 June, 2011

Venue: R101, North Building, Institute of Microbiology, CAS

Abstract: The MHCII presentation pathway is tightly regulated in dendritic cells (DCs); yet how the key modulators of MHCII presentation, H2-M and H2-O, are affected in different DC subsets in response to maturation is unknown. Here we show that H2-O is markedly downregulated in vivo in mouse CD8α- DCs in response to a broad array of TLR agonists. CD8α+ DCs also downregulated H2-O in response to TLR-agonists, but to a much lesser extent. H2-M levels were slightly down-modulated in both CD8α- and CD8α+ DCs. As a consequence, H2-M:H2-O ratios significantly increased for CD8α- but not CD8α+ DCs. The TLR-mediated downregulation was DC-specific, as B cells did not show significant H2-O and H2-M downregulation. TLR4 signaling was required to mediate DC H2-O downregulation in response to LPS. Finally, our studies showed that the mechanism of H2-O downregulation was likely due to direct protein degradation of H2-O as well as down regulation of H2-O mRNA levels. Conservation of H2-O downregulation by multiple TLR pathways suggests that the control of H2-O and H2-M levels serves an important role in DC MHCII presentation. The differential H2-O and H2-M modulation after DC maturation support the proposed roles of CD8α- dendritic cells in initiating CD4-restricted immune responses by optimal MHCII presentation and CD8α+ DCs in promoting immune tolerance via presentation of low levels of MHCII-peptide.