Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells

Harriff, Melanie J.; Karamooz, Elham; Burr, Ansen; Grant, Wilmon F.; Canfield, Elizabeth T.; Sorensen, Michelle L.; Moita, Luis F.; Lewinsohn, David M.

Publication

Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells

2016-03-31Journal article

dc.contributor.author	Harriff, Melanie J.
dc.contributor.author	Karamooz, Elham
dc.contributor.author	Burr, Ansen
dc.contributor.author	Grant, Wilmon F.
dc.contributor.author	Canfield, Elizabeth T.
dc.contributor.author	Sorensen, Michelle L.
dc.contributor.author	Moita, Luis F.
dc.contributor.author	Lewinsohn, David M.
dc.date.accessioned	2016-04-04T10:43:54Z
dc.date.available	2016-04-04T10:43:54Z
dc.date.issued	2016-03-31
dc.description.abstract	Mucosal-Associated Invariant T (MAIT) cells, present in high frequency in airway and other mucosal tissues, have Th1 effector capacity positioning them to play a critical role in the early immune response to intracellular pathogens, including Mycobacterium tuberculosis (Mtb). MR1 is a highly conserved Class I-like molecule that presents vitamin B metabolites to MAIT cells. The mechanisms for loading these ubiquitous small molecules are likely to be tightly regulated to prevent inappropriate MAIT cell activation. To define the intracellular localization of MR1, we analyzed the distribution of an MR1-GFP fusion protein in antigen presenting cells. We found that MR1 localized to endosomes and was translocated to the cell surface upon addition of 6-formyl pterin (6-FP). To understand the mechanisms by which MR1 antigens are presented, we used a lentiviral shRNA screen to identify trafficking molecules that are required for the presentation of Mtb antigen to HLA-diverse T cells. We identified Stx18, VAMP4, and Rab6 as trafficking molecules regulating MR1-dependent MAIT cell recognition of Mtb-infected cells. Stx18 but not VAMP4 or Rab6 knockdown also resulted in decreased 6-FP-dependent surface translocation of MR1 suggesting distinct pathways for loading of exogenous ligands and intracellular mycobacterially-derived ligands. We postulate that endosome-mediated trafficking of MR1 allows for selective sampling of the intracellular environment.	pt_PT
dc.description.sponsorship	Career Development Award: (#IK2 CX000538); U.S. Department of Veterans Affairs Clinical Sciences Research and Development Program (MJH); U.S.Department of Veterans Affairs Biomedical Laboratory Research and Development Program (DML) Merit Award: (#I01 BX000533); American Lung Association: (RT-350058).	pt_PT
dc.identifier.citation	Harriff MJ, Karamooz E, Burr A, Grant WF, Canfield ET, Sorensen ML, et al. (2016) Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells. PLoS Pathog 12(3): e1005524. doi:10.1371/journal. ppat.1005524	pt_PT
dc.identifier.doi	10.1371/journal.ppat.1005524	pt_PT
dc.identifier.uri	http://hdl.handle.net/10400.7/577
dc.language.iso	eng	pt_PT
dc.peerreviewed	yes	pt_PT
dc.publisher	PLOS	pt_PT
dc.relation.publisherversion	http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005524	pt_PT
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	pt_PT
dc.subject	Mycobacterium tuberculosis	pt_PT
dc.subject	T cells	pt_PT
dc.subject	Small interfering RNAs	pt_PT
dc.subject	Antigen-presenting cells	pt_PT
dc.subject	Enzyme-linked immunoassays	pt_PT
dc.subject	Cloning	pt_PT
dc.subject	Intracellular pathogens	pt_PT
dc.subject	Antigen presentation	pt_PT
dc.title	Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells	pt_PT
dc.type	journal article
dspace.entity.type	Publication
oaire.citation.endPage	19	pt_PT
oaire.citation.issue	3	pt_PT
oaire.citation.startPage	1	pt_PT
oaire.citation.title	Plos Pathogens	pt_PT
oaire.citation.volume	12	pt_PT
rcaap.rights	openAccess	pt_PT
rcaap.type	article	pt_PT