Limited diversity of peptides related to an alloreactive T cell epitope inthe HLA-B27-bound peptide repertoire results from restrictions at multiplesteps along the processing-loading pathway
A. Paradela et al., Limited diversity of peptides related to an alloreactive T cell epitope inthe HLA-B27-bound peptide repertoire results from restrictions at multiplesteps along the processing-loading pathway, J IMMUNOL, 164(1), 2000, pp. 329-337
The influence of various factors along the processing-loading pathway in li
miting the diversity of HLA-B27-bound peptides around a core protein sequen
ce was analyzed. The C5 proteasome subunit-derived RRFFPYYV and RRFFPYYVY p
eptides are natural B*2705 ligands, The octamer is an allospecific CTL epit
ope, Digestion of a 27-mer fragment of C5 revealed that both ligands are ge
nerated 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 residu
es 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 t
he absence of four of the six: peptides, The two remaining differed from th
e natural octamer or nonamer ligands only by an additional N-terminal Ser r
esidue. Their stability in complex with B*2705 was lower than the respectiv
e natural ligands, raising the possibility that N-terminal trimming might h
ave favored a shift toward the more stable peptides, The results suggest th
at the B*2705-bound peptide repertoire has a highly restricted diversity ar
ound a core alloantigenic sequence. This is not explained by a single bottl
eneck feature, but by multiple factors, including proteasomal generation, T
AP-binding motifs, MHC-binding efficiency, and perhaps optimized stability
through N-terminal trimming. Tapasin-dependent restrictions, although not e
xcluded, were not required to explain the absence in vivo of the particular
peptide set in this study.