Bacterial proteins can be processed by macrophages in a transporter associated with antigen processing-independent, cysteine protease-dependent manner for presentation by MHC class I molecules

Daniel J. Campbell, Thomas Serwold, Nilabh Shastri

Research output: Contribution to journalArticle

Abstract

MHC class I molecules present peptides derived primarily from endogenously synthesized proteins on the cell surface as ligands for CD8+ T cells. However, CD8+ T cell responses to extracellular bacteria, virus- infected, or tumor cells can also be elicited because certain professional APC can generate peptide/MHC class I (MHC-I) complexes from exogenous sources. Whether the peptide/MHC-I complexes are generated because the exogenous proteins enter the classical cytosolic, TAP-dependent MHC-I processing pathway or an alternate pathway is controversial. Here we analyze the generation of peptide/MHC-I complexes from recombinant Escherichia coli as an exogenous Ag source that could be delivered to the phagosomes or directly into the cytosol. We show that peritoneal and bone marrow macrophages generate peptide/MHC-I complexes by the classical as well as an alternate, but relatively less efficient, TAP-independent pathway. Using a novel method to detect proteolytic intermediates we show that the generation of the optimal MHC-I binding peptide in the alternate pathway requires cysteine as well as other protease(s). This alternate TAP-independent pathway also operates in vivo and provides a potential mechanism for eliciting CD8+ T cell responses to exogenous Ags.

Original languageEnglish (US)
Pages (from-to)168-175
Number of pages8
JournalJournal of Immunology
Volume164
Issue number1
DOIs
StatePublished - Jan 1 2000
Externally publishedYes

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Bacterial Proteins
Cysteine Proteases
Antigen Presentation
Macrophages
Peptides
T-Lymphocytes
Phagosomes
Cytosol
Cysteine
Membrane Proteins
Peptide Hydrolases
Bone Marrow
Escherichia coli
Ligands
Viruses
Bacteria
Neoplasms
Proteins

ASJC Scopus subject areas

  • Immunology

Cite this

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title = "Bacterial proteins can be processed by macrophages in a transporter associated with antigen processing-independent, cysteine protease-dependent manner for presentation by MHC class I molecules",
abstract = "MHC class I molecules present peptides derived primarily from endogenously synthesized proteins on the cell surface as ligands for CD8+ T cells. However, CD8+ T cell responses to extracellular bacteria, virus- infected, or tumor cells can also be elicited because certain professional APC can generate peptide/MHC class I (MHC-I) complexes from exogenous sources. Whether the peptide/MHC-I complexes are generated because the exogenous proteins enter the classical cytosolic, TAP-dependent MHC-I processing pathway or an alternate pathway is controversial. Here we analyze the generation of peptide/MHC-I complexes from recombinant Escherichia coli as an exogenous Ag source that could be delivered to the phagosomes or directly into the cytosol. We show that peritoneal and bone marrow macrophages generate peptide/MHC-I complexes by the classical as well as an alternate, but relatively less efficient, TAP-independent pathway. Using a novel method to detect proteolytic intermediates we show that the generation of the optimal MHC-I binding peptide in the alternate pathway requires cysteine as well as other protease(s). This alternate TAP-independent pathway also operates in vivo and provides a potential mechanism for eliciting CD8+ T cell responses to exogenous Ags.",
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N2 - MHC class I molecules present peptides derived primarily from endogenously synthesized proteins on the cell surface as ligands for CD8+ T cells. However, CD8+ T cell responses to extracellular bacteria, virus- infected, or tumor cells can also be elicited because certain professional APC can generate peptide/MHC class I (MHC-I) complexes from exogenous sources. Whether the peptide/MHC-I complexes are generated because the exogenous proteins enter the classical cytosolic, TAP-dependent MHC-I processing pathway or an alternate pathway is controversial. Here we analyze the generation of peptide/MHC-I complexes from recombinant Escherichia coli as an exogenous Ag source that could be delivered to the phagosomes or directly into the cytosol. We show that peritoneal and bone marrow macrophages generate peptide/MHC-I complexes by the classical as well as an alternate, but relatively less efficient, TAP-independent pathway. Using a novel method to detect proteolytic intermediates we show that the generation of the optimal MHC-I binding peptide in the alternate pathway requires cysteine as well as other protease(s). This alternate TAP-independent pathway also operates in vivo and provides a potential mechanism for eliciting CD8+ T cell responses to exogenous Ags.

AB - MHC class I molecules present peptides derived primarily from endogenously synthesized proteins on the cell surface as ligands for CD8+ T cells. However, CD8+ T cell responses to extracellular bacteria, virus- infected, or tumor cells can also be elicited because certain professional APC can generate peptide/MHC class I (MHC-I) complexes from exogenous sources. Whether the peptide/MHC-I complexes are generated because the exogenous proteins enter the classical cytosolic, TAP-dependent MHC-I processing pathway or an alternate pathway is controversial. Here we analyze the generation of peptide/MHC-I complexes from recombinant Escherichia coli as an exogenous Ag source that could be delivered to the phagosomes or directly into the cytosol. We show that peritoneal and bone marrow macrophages generate peptide/MHC-I complexes by the classical as well as an alternate, but relatively less efficient, TAP-independent pathway. Using a novel method to detect proteolytic intermediates we show that the generation of the optimal MHC-I binding peptide in the alternate pathway requires cysteine as well as other protease(s). This alternate TAP-independent pathway also operates in vivo and provides a potential mechanism for eliciting CD8+ T cell responses to exogenous Ags.

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