Modulation on immunogenicity by HLA‐B27 subtype polymorphism

Abstract

Cells from the same HLA-B27- individual, PA, were stimulated in vitro in primary mixed lymphocyte culture, with either B*2705+ or B*2704+ lymphoblastoid cell lines, in independent experiments. Cytolytic T lymphocytes (CTL) were cloned at limiting dilution and the clones obtained were screened for anti-B27 alloreactivity. Most of the CTL clones generated against the B*2705+ stimulator cells were directed against the B*2705 antigen. In contrast, no anti-B27 CTL clones were found among those derived against the B*2704+ stimulator cells. This was not due to a poor cytotoxic response against these cells because a large proportion of the T cell clones derived from this stimulation were cytotoxic. B2704 differs from B*2705 by only two amino acid changes at positions 77 and 152. Previous studies (Aparacio, P. et al., Eur. J. Immunol. 1988.18: 203) have shown that none of the anti-B*2705 CTL clones derived from donor PA and amenable to detailed characterization cross-reacted with B*2704, suggesting that most of this cytotoxic response was directed against an immunodominant determinant contributed for by residues 77 and/or 152 from B*2705. The present results further suggest that the changes at these positions in B*2704 alter this determinant in such a way that B*2704 becomes less immunogenic for the particular individual PA. Furthermore, a similar poor anti-B*2704 CTL response was obtained from a second B27- responder individual, AE, stimulated with another B2704+ cell line. The single anti-B*2704 CTL clone, 64.8P, isolated from this second individual, displayed an unusual reaction pattern in that it cross-reacted with all B27 subtypes with changes only at or close to positions 77 and 152, including B*2705. Significantly, the only HLA-B27 subtype that was not recognized by CTL 64.8P was B*2703, which differs from B*2705 only at residue 59. This residue is located in the three-dimensional structure at the opposite end from residues 77 and 152 at the surface of the antigen-binding groove of the class I molecule. Thus, the area around residues 77 and 152 is not an essential part of the epitope recognized by CTL 64.8P.

Recognition of Distinct Cross-Reactive Virus-Specific CD8+ T Cells Reveals a Unique TCR Signature in a Clinical Setting

“…The fact that LTR5 was "lucky" not to receive one of the immunogenic HLA-B27 alleles is a chance event, and their uneventful clinical course posttransplant supports this observation. Interestingly, studies of the autoimmune disease ankylosing spondylitis have shown B*27:04 to be more immunogenic as a risk factor compared with B*27:02 and B*27:05, with other B27 alleles being identified as either protective or as having no association with susceptibility (59,60).…”

T cell receptor V beta gene usage in a human alloreactive response. Shared structural features among HLA-B27-specific T cell clones.

“…Thus, none of the 11 anti-B*2705 CTL clones recognized B*2701, B*2704, or B*2706 . The anti-B*2704 CTL clone 64 .8P reacted with all B27 subtypes except B*2703 (18) . Most CTL clones were different from one another when tested with the mutants (10) .…”

“…The following anti-B*2705 CTL clones were derived from each responder: from donor PA (HLA-A24, w33; B35,39), CTL 28 and 40 (17) ; from donor DL (HLA-A29, 31 ; B39, 44), CTL 64DRF, 67DRF, 102DRF, 172DRF, and 212DRD ; from donor GM (HLA-Al, 24 ; B7, 8), CTL GM7, 5A2, and 17A2 ; from donor BG (HLA-A2; B5, 7), CTL G36 (10) . One additional clone, CTL 64 .8P, was obtained from yet another HLA-B27 -individual against a B*2704' LCL (18) . In addition, eight CTL clones not reactive with HLA-B27, but otherwise uncharacterized, were used.…”

“…The anti-B*2705 CTL clones could be classified into three groups (Table I) on the basis of their reactivity with HLA-B27 subtypes (10,17) (18) . Most CTL clones were different from one another when tested with the mutants (10) .…”