The Mycobacterium tuberculosis phagosome is a HLA-I processing competent organelle.
Mycobacterium tuberculosis (Mtb) resides in a long-lived phagosomal compartment that resists maturation. The manner by which Mtb antigens are processed and presented on MHC Class I molecules is poorly understood. Using human dendritic cells and IFN-gamma release by CD8(+) T cell clones, we examined...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-04-01
|
| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC2661020?pdf=render |
| _version_ | 1818138131635896320 |
|---|---|
| author | Jeff E Grotzke Melanie J Harriff Anne C Siler Dawn Nolt Jacob Delepine Deborah A Lewinsohn David M Lewinsohn |
| author_facet | Jeff E Grotzke Melanie J Harriff Anne C Siler Dawn Nolt Jacob Delepine Deborah A Lewinsohn David M Lewinsohn |
| author_sort | Jeff E Grotzke |
| collection | DOAJ |
| description | Mycobacterium tuberculosis (Mtb) resides in a long-lived phagosomal compartment that resists maturation. The manner by which Mtb antigens are processed and presented on MHC Class I molecules is poorly understood. Using human dendritic cells and IFN-gamma release by CD8(+) T cell clones, we examined the processing and presentation pathway for two Mtb-derived antigens, each presented by a distinct HLA-I allele (HLA-Ia versus HLA-Ib). Presentation of both antigens is blocked by the retrotranslocation inhibitor exotoxin A. Inhibitor studies demonstrate that, after reaching the cytosol, both antigens require proteasomal degradation and TAP transport, but differ in the requirement for ER-golgi egress and new protein synthesis. Specifically, presentation by HLA-B8 but not HLA-E requires newly synthesized HLA-I and transport through the ER-golgi. Phenotypic analysis of the Mtb phagosome by flow organellometry revealed the presence of Class I and loading accessory molecules, including TAP and PDI. Furthermore, loaded HLA-I:peptide complexes are present within the Mtb phagosome, with a pronounced bias towards HLA-E:peptide complexes. In addition, protein analysis also reveals that HLA-E is enriched within the Mtb phagosome compared to HLA-A2. Together, these data suggest that the phagosome, through acquisition of ER-localized machinery and as a site of HLA-I loading, plays a vital role in the presentation of Mtb-derived antigens, similar to that described for presentation of latex bead-associated antigens. This is, to our knowledge, the first description of this presentation pathway for an intracellular pathogen. Moreover, these data suggest that HLA-E may play a unique role in the presentation of phagosomal antigens. |
| first_indexed | 2024-12-11T10:07:19Z |
| format | Article |
| id | doaj.art-0677eb531b464baab66320e1c516f807 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-11T10:07:19Z |
| publishDate | 2009-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-0677eb531b464baab66320e1c516f8072022-12-22T01:11:54ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742009-04-0154e100037410.1371/journal.ppat.1000374The Mycobacterium tuberculosis phagosome is a HLA-I processing competent organelle.Jeff E GrotzkeMelanie J HarriffAnne C SilerDawn NoltJacob DelepineDeborah A LewinsohnDavid M LewinsohnMycobacterium tuberculosis (Mtb) resides in a long-lived phagosomal compartment that resists maturation. The manner by which Mtb antigens are processed and presented on MHC Class I molecules is poorly understood. Using human dendritic cells and IFN-gamma release by CD8(+) T cell clones, we examined the processing and presentation pathway for two Mtb-derived antigens, each presented by a distinct HLA-I allele (HLA-Ia versus HLA-Ib). Presentation of both antigens is blocked by the retrotranslocation inhibitor exotoxin A. Inhibitor studies demonstrate that, after reaching the cytosol, both antigens require proteasomal degradation and TAP transport, but differ in the requirement for ER-golgi egress and new protein synthesis. Specifically, presentation by HLA-B8 but not HLA-E requires newly synthesized HLA-I and transport through the ER-golgi. Phenotypic analysis of the Mtb phagosome by flow organellometry revealed the presence of Class I and loading accessory molecules, including TAP and PDI. Furthermore, loaded HLA-I:peptide complexes are present within the Mtb phagosome, with a pronounced bias towards HLA-E:peptide complexes. In addition, protein analysis also reveals that HLA-E is enriched within the Mtb phagosome compared to HLA-A2. Together, these data suggest that the phagosome, through acquisition of ER-localized machinery and as a site of HLA-I loading, plays a vital role in the presentation of Mtb-derived antigens, similar to that described for presentation of latex bead-associated antigens. This is, to our knowledge, the first description of this presentation pathway for an intracellular pathogen. Moreover, these data suggest that HLA-E may play a unique role in the presentation of phagosomal antigens.http://europepmc.org/articles/PMC2661020?pdf=render |
| spellingShingle | Jeff E Grotzke Melanie J Harriff Anne C Siler Dawn Nolt Jacob Delepine Deborah A Lewinsohn David M Lewinsohn The Mycobacterium tuberculosis phagosome is a HLA-I processing competent organelle. PLoS Pathogens |
| title | The Mycobacterium tuberculosis phagosome is a HLA-I processing competent organelle. |
| title_full | The Mycobacterium tuberculosis phagosome is a HLA-I processing competent organelle. |
| title_fullStr | The Mycobacterium tuberculosis phagosome is a HLA-I processing competent organelle. |
| title_full_unstemmed | The Mycobacterium tuberculosis phagosome is a HLA-I processing competent organelle. |
| title_short | The Mycobacterium tuberculosis phagosome is a HLA-I processing competent organelle. |
| title_sort | mycobacterium tuberculosis phagosome is a hla i processing competent organelle |
| url | http://europepmc.org/articles/PMC2661020?pdf=render |
| work_keys_str_mv | AT jeffegrotzke themycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT melaniejharriff themycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT annecsiler themycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT dawnnolt themycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT jacobdelepine themycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT deborahalewinsohn themycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT davidmlewinsohn themycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT jeffegrotzke mycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT melaniejharriff mycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT annecsiler mycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT dawnnolt mycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT jacobdelepine mycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT deborahalewinsohn mycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle AT davidmlewinsohn mycobacteriumtuberculosisphagosomeisahlaiprocessingcompetentorganelle |