TLR agonists downregulate H2-O in CD8alpha- dendritic cells

J Immunol. 2011 Oct 15;187(8):4151-60. doi: 10.4049/jimmunol.1003137. Epub 2011 Sep 14.

Abstract

Peptide loading of MHC class II (MHCII) molecules is catalyzed by the nonclassical MHCII-related molecule H2-M. H2-O, another MHCII-like molecule, associates with H2-M and modulates H2-M function. 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. In this study, we show that H2-O is markedly downregulated in vivo in mouse CD8α(-) DCs in response to a broad array of TLR agonists. In contrast, CD8α(+) DCs only modestly downregulated H2-O in response to TLR agonists. H2-M levels were slightly downmodulated in both CD8α(-) and CD8α(+) DCs. As a consequence, H2-M/H2-O ratios significantly increased for CD8α(-) but not for 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 downregulation of H2-O mRNA levels. The differential H2-O and H2-M modulation after DC maturation supports the proposed roles of CD8α(-) DCs in initiating CD4-restricted immune responses by optimal MHCII presentation and of CD8α(+) DCs in promoting immune tolerance via presentation of low levels of MHCII-peptide.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen Presentation / immunology
  • CD8 Antigens / immunology
  • CD8 Antigens / metabolism*
  • Cell Separation
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Down-Regulation
  • Flow Cytometry
  • Histocompatibility Antigens Class II / biosynthesis*
  • Histocompatibility Antigens Class II / immunology
  • Immune Tolerance / immunology
  • Immunoblotting
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptors / agonists

Substances

  • CD8 Antigens
  • CD8alpha antigen
  • H-2O antigen
  • H2-M antigens
  • Histocompatibility Antigens Class II
  • Toll-Like Receptors