HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paradela, A. Articles by López de Castro, J. A. Search for Related Content PubMed PubMed Citation Articles by Paradela, A. Articles by López de Castro, J. A.

Limited Diversity of Peptides Related to an Alloreactive T Cell Epitope in the HLA-B27-Bound Peptide Repertoire Results from Restrictions at Multiple Steps Along the Processing-Loading Pathway¹

Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Facultad de Ciencias, Madrid, Spain

The influence of various factors along the processing-loading pathway in limiting the diversity of HLA-B27-bound peptides around a core protein sequence was analyzed. The C5 proteasome subunit-derived RRFFPYYV and RRFFPYYVY peptides are natural B*2705 ligands. The octamer is an allospecific CTL epitope. Digestion of a 27-mer fragment of C5 revealed that both ligands are generated from this precursor substrate with the 20S proteasome in vitro in a ratio comparable to that in the B*2705-bound peptide pool. The C5 sequence allowed to derive a nested set of six additional peptides with 8–11 residues containing the core octamer sequence and the Arg2 motif of HLA-B27, none of which was found in the B27-bound pool. Together, low proteasomal yield, disfavored TAP-binding motifs, and low affinity for B*2705 accounted for the absence of four of the six peptides. The two remaining differed from the natural octamer or nonamer ligands only by an additional N-terminal Ser residue. Their stability in complex with B*2705 was lower than the respective natural ligands, raising the possibility that N-terminal trimming might have favored a shift toward the more stable peptides. The results suggest that the B*2705-bound peptide repertoire has a highly restricted diversity around a core alloantigenic sequence. This is not explained by a single bottleneck feature, but by multiple factors, including proteasomal generation, TAP-binding motifs, MHC-binding efficiency, and perhaps optimized stability through N-terminal trimming. Tapasin-dependent restrictions, although not excluded, were not required to explain the absence in vivo of the particular peptide set in this study.

This article has been cited by other articles:

				J. J. Cragnolini, N. Garcia-Medel, and J. A. Lopez de Castro Endogenous Processing and Presentation of T-cell Epitopes from Chlamydia trachomatis with Relevance in HLA-B27-associated Reactive Arthritis Mol. Cell. Proteomics, August 1, 2009; 8(8): 1850 - 1859. [Abstract] [Full Text] [PDF]

				P. Gomez, C. Mavian, B. Galocha, N. Garcia-Medel, and J. A. Lopez de Castro Presentation of Cytosolically Stable Peptides by HLA-B27 Is Not Dependent on the Canonic Interactions of N-Terminal Basic Residues in the A Pocket J. Immunol., January 1, 2009; 182(1): 446 - 455. [Abstract] [Full Text] [PDF]

				J. J. Cragnolini and J. A. L. de Castro Identification of Endogenously Presented Peptides from Chlamydia trachomatis with High Homology to Human Proteins and to a Natural Self-ligand of HLA-B27 Mol. Cell. Proteomics, January 1, 2008; 7(1): 170 - 180. [Abstract] [Full Text] [PDF]

				M. Marcilla, J. J. Cragnolini, and J. A. Lopez de Castro Proteasome-independent HLA-B27 Ligands Arise Mainly from Small Basic Proteins Mol. Cell. Proteomics, May 1, 2007; 6(5): 923 - 938. [Abstract] [Full Text] [PDF]

				E. Merino, V. Montserrat, A. Paradela, and J. A.L. de Castro Two HLA-B14 Subtypes (B*1402 and B*1403) Differentially Associated with Ankylosing Spondylitis Differ Substantially in Peptide Specificity but Have Limited Peptide and T-cell Epitope Sharing with HLA-B27 J. Biol. Chem., October 28, 2005; 280(43): 35868 - 35880. [Abstract] [Full Text] [PDF]

				L. Sesma, B. Galocha, M. Vazquez, A. W. Purcell, M. Marcilla, J. McCluskey, and J. A. L. de Castro Qualitative and Quantitative Differences in Peptides Bound to HLA-B27 in the Presence of Mouse versus Human Tapasin Define a Role for Tapasin as a Size-Dependent Peptide Editor J. Immunol., June 15, 2005; 174(12): 7833 - 7844. [Abstract] [Full Text] [PDF]

				L. Sesma, I. Alvarez, M. Marcilla, A. Paradela, and J. A. L. de Castro Species-specific Differences in Proteasomal Processing and Tapasin-mediated Loading Influence Peptide Presentation by HLA-B27 in Murine Cells J. Biol. Chem., November 21, 2003; 278(47): 46461 - 46472. [Abstract] [Full Text] [PDF]

				M. Ramos, I. Alvarez, L. Sesma, A. Logean, D. Rognan, and J. A. Lopez de Castro Molecular Mimicry of an HLA-B27-derived Ligand of Arthritis-linked Subtypes with Chlamydial Proteins J. Biol. Chem., September 27, 2002; 277(40): 37573 - 37581. [Abstract] [Full Text] [PDF]

				M. Ramos, A. Paradela, M. Vazquez, A. Marina, J. Vazquez, and J. A. Lopez de Castro Differential Association of HLA-B*2705 and B*2709 to Ankylosing Spondylitis Correlates with Limited Peptide Subsets but Not with Altered Cell Surface Stability J. Biol. Chem., August 2, 2002; 277(32): 28749 - 28756. [Abstract] [Full Text] [PDF]

				L. Sesma, V. Montserrat, J. R. Lamas, A. Marina, J. Vazquez, and J. A. L. de Castro The Peptide Repertoires of HLA-B27 Subtypes Differentially Associated to Spondyloarthropathy (B*2704 and B*2706) Differ by Specific Changes at Three Anchor Positions J. Biol. Chem., May 3, 2002; 277(19): 16744 - 16749. [Abstract] [Full Text] [PDF]

				J. Yague, A. Marina, J. Vazquez, and J. A. Lopez de Castro Major Histocompatibility Complex Class I Molecules Bind Natural Peptide Ligands Lacking the Amino-terminal Binding Residue in Vivo J. Biol. Chem., November 16, 2001; 276(47): 43699 - 43707. [Abstract] [Full Text] [PDF]

				B. Korber, B. Gaschen, K. Yusim, R. Thakallapally, C. Kesmir, and V. Detours Evolutionary and immunological implications of contemporary HIV-1 variation Br. Med. Bull., September 1, 2001; 58(1): 19 - 42. [Abstract] [Full Text] [PDF]

				I. Alvarez, L. Sesma, M. Marcilla, M. Ramos, M. Marti, E. Camafeita, and J. A. L. de Castro Identification of Novel HLA-B27 Ligands Derived from Polymorphic Regions of Its Own or Other Class I Molecules Based on Direct Generation by 20 S Proteasome J. Biol. Chem., August 24, 2001; 276(35): 32729 - 32737. [Abstract] [Full Text] [PDF]

				I. Alvarez, M. Marti, J. Vazquez, E. Camafeita, S. Ogueta, and J. A. Lopez de Castro The Cys-67 Residue of HLA-B27 Influences Cell Surface Stability, Peptide Specificity, and T-cell Antigen Presentation J. Biol. Chem., December 21, 2001; 276(52): 48740 - 48747. [Abstract] [Full Text] [PDF]