Allele-dependent variations in permissive HLA-B antigen presentation pathways.

<p>In the conventional pathway operative in normal cells (A), TAP-dependent peptides are presented by the majority of HLA-B allotypes, although members of the B7 supertype may also present optimal and suboptimal peptides from TAP-independent sources, due to mismatch between their peptide-binding preferences and TAP transport specificity. While expression levels of many allotypes are strongly reduced by tapasin or TAP deficiency, some allotypes are relatively resistant to the deficiency of these factors (B and C). In particular, B*18:01, B*44:05, B*40:01, B*35:01, B*35:03 and B*15:01 are detectable at the highest levels in tapasin-deficient cells (B), based on higher stabilities of the peptide-deficient forms and/or high peptide-loading efficiencies (Ref. 22). B*57:03, B*35:03, B*15:01 and B*35:01 (RIT-HLA-B) are detected at the highest levels under TAP-deficiency conditions (C). The high expression of RIT-HLA-B under TAP-deficiency conditions is mediated by the synergy between their high intrinsic stability, high peptide loading efficiency and generally broader peptide repertoires, particularly for peptides present within unconventional sources such as signal sequences. The strong reduction in the ER peptide levels under TAP-deficiency conditions contributes to the suboptimal loading and cell surface peptide receptivity of RIT-HLA-B. The ER quality control system for the retrieval of suboptimally loaded RIT-HLA-B molecules is imperfect, and alternative (non-Golgi) pathways may exist for transport of suboptimally loaded RIT-HLA-B molecules to the cell surface. RIT-HLA-B allotypes are expected to induce stronger CD8<sup>+</sup> T cell responses in the context of viruses that inhibit TAP, but weaker NK responses. Conversely, other non-RIT HLA-B are expected to induce stronger NK responses but weaker CD8<sup>+</sup> T cell responses, following infections with viruses that inhibit TAP.</p>