The Rat cim Effect: TAP Allele-Dependent Changes in a Class I MHC Anchor Motif and Evidence Against C-Terminal Trimming of Peptides in the ER

Powis, Simon J.; Young, Lesley; Joly, Etienne; Barker, Paul D.; Richardson, Louise; Brandt, Remco P; Melief, Cornelis J.M.; Howard, Jonathan C.; Butcher, Geoffrey W.

doi:10.1016/s1074-7613(00)80680-9

Cited by 111 publications

(64 citation statements)

References 36 publications

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“…This suggests that there is little carboxypeptidase activity available for Ag trimming in the secretory pathway (40). From the rat cim model, it was known that the carboxypeptidase activity that removes hydrophobic residues from the carboxyl termini of antigenic peptides is essentially lacking in the ER (41). Our results now show that carboxy-or endopeptidases that remove some polar and charged residues are also extremely rate limiting for Ag presentation in the secretory pathway.…”

Section: Discussionmentioning

confidence: 61%

Furin-Processed Antigens Targeted to the Secretory Route Elicit Functional TAP1−/−CD8+ T Lymphocytes In Vivo

Medina

Ramos²,

Iborra³

et al. 2009

The Journal of Immunology

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Most pathogen-derived peptides recognized by CD8+ CTL are produced by proteasomes and delivered to the endoplasmic reticulum by the TAP transporters associated with Ag processing. Alternative proteases also produce antigenic peptides, but their actual relevance is unclear. There is a need to quantify the contribution of these supplementary pathways in vitro and in vivo. A well-defined TAP-independent secretory route of Ag processing involves the trans-Golgi network protease furin. Quantitation of this route by using OVA constructs encoded by vaccinia viruses indicates that it provides approximately one-third of all surface complexes of peptide and MHC class I molecules. Generation of the epitope carboxyl terminus is a dramatic rate-limiting step, since bypassing it increased efficiency by at least 1000-fold. Notably, the secretory construct activated a similar percentage of Ag-specific CD8+ T cells in wild type as in TAP1-deficient mice, which allow only secretory routes but which have a 10- to 20-fold smaller CD8 compartment. Moreover, these TAP1−/− OVA-specific CD8+ T lymphocytes accomplished elimination of epitope-bearing cells in vivo. The results obtained with this experimental system underscore the potential of secretory pathways of MHC class I Ag presentation to elicit functional CD8+ T lymphocytes in vivo and support the hypothesis that noncytosolic processing mechanisms may compensate in vivo for the lack of proteasome participation in Ag processing in persons genetically deficient in TAP and thus contribute to pathogen control.

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Section: Discussionmentioning

confidence: 61%

Furin-Processed Antigens Targeted to the Secretory Route Elicit Functional TAP1−/−CD8+ T Lymphocytes In Vivo

Medina

Ramos²,

Iborra³

et al. 2009

The Journal of Immunology

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show abstract

“…Distinctive allelic lineages of TAP2 and linkage disequilibrium between class Ia and TAP2 genes were previously reported in rats [8,9] and chickens [10]. Peptides transported by the 'restrictive' rat TAP2B presumably can be loaded onto TAP2B-linked class I molecules more efficiently [11][12][13]. A similar phenomenon is believed to occur in chickens, in which there is extremely tight genetic linkage between class Ia and TAP1/2 [10,14], and TAP1 lineages have also been described in hamsters [15].…”

Section: Introductionmentioning

confidence: 67%

Two highly divergent ancient allelic lineages of the transporter associated with antigen processing (TAP) gene in Xenopus: further evidence for co‐evolution among MHC class I region genes

et al. 2003

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In the frog Xenopus, MHC class I antigen presentation and processing genes (the immunoproteasome LMP2 and LMP7 and the transporter TAP1 and TAP2) seem to be closely linked in a primordial organization. Two distinct lineages of class Ia and LMP7 loci were previously identified, thus strongly suggesting co-evolution among 'class I region' genes. We now show that the Xenopus MHC 'class I region' lies between class II and class III genes and we have isolated two distinct alleles at both the TAP1 and TAP2 loci. The alleles at each locus are remarkably divergent from each other and phylogenetic tree analysis revealed in both cases that they diverged from each other 60-100 million years ago (MYA). For lineage-frequency and linkage analysis, 25 wild-caught X. laevis and 16 X. tropicalis were examined. The two lineages were present in different frequencies for X. laevis and X. tropicalis. Nevertheless, in all cases, the LMP7, TAP1, and TAP2 lineages were found in a set comprising one of the two lineages. Furthermore, like the LMP7 lineages, the TAP lineages were detected in most Xenopus species that diverged from a common ancestor 80-100 MYA, suggesting that the 'class I region' biallelic lineages are under balancing selection.

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“…Conflicting results have been reported when different model systems are used. Both the observation of the rat cim effect and results of some ER-targeting experiments indicate a lack of C-terminal trimming in the ER (13,24,43). Other ER targeting studies and the identification of TAP-I leader-derived peptides suggest that significant processing occurs at both ends of ER peptides (25)(26)(27)30).…”

Section: Ability Of Er Proteases To Process the Full-length D D Leadementioning

confidence: 97%

Factors Controlling the Trafficking and Processing of a Leader-Derived Peptide Presented by Qa-1

Bai

Aldrich

Forman

2000

The Journal of Immunology

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Many leader-derived peptides require TAP for presentation by class I molecules. This TAP dependence can either be ascribed to the inability of proteases resident in the endoplasmic reticulum (ER) to trim leader peptide precursors into the appropriate epitope or the failure of a portion of the leader segment to gain access to the lumen of the ER. Using the Qa-1 binding epitope, Qdm derived from a class Ia leader as a model, we show that many cell types lack ER protease activity to trim this peptide at its C terminus. However, both T1 and T2 cells contain appropriate protease activity to process the full length Dd leader (DL) when introduced into the ER lumen. Nevertheless, both T1 cells treated with the TAP inhibitor ICP47 and TAP− T2 cells fail to present this epitope from either the intact Dd molecule or a minigene encoding the DL. This indicates that the portion of the leader containing Qdm does not gain access to the ER. However, changing the Arg at P7 of the DL to a Cys can alter its trafficking and allows for TAP-independent presentation of the Qdm epitope.

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The Rat cim Effect: TAP Allele-Dependent Changes in a Class I MHC Anchor Motif and Evidence Against C-Terminal Trimming of Peptides in the ER

Cited by 111 publications

References 36 publications

Furin-Processed Antigens Targeted to the Secretory Route Elicit Functional TAP1−/−CD8+ T Lymphocytes In Vivo

Furin-Processed Antigens Targeted to the Secretory Route Elicit Functional TAP1−/−CD8+ T Lymphocytes In Vivo

Two highly divergent ancient allelic lineages of the transporter associated with antigen processing (TAP) gene in Xenopus: further evidence for co‐evolution among MHC class I region genes

Factors Controlling the Trafficking and Processing of a Leader-Derived Peptide Presented by Qa-1

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