Despite extensive research, it remains unclear why a small proportion of HLA- B27(+) individuals develop spondyloarthropathies (SpA). Because the function of HLA-B27, as a major histocompatibility complex (MHC) class I molecule, is peptide presentation to CD8(+) T cells, research has concentrated on the role of HLA-B27 as a restriction element for CD8(+) cytotoxic T lymphocytes in pathogenesis. However, findings in the B27-transgenic animal models, together with the identification of unusual processing and presentation features of HLA-B27, have raised alternative hypotheses for the pathogenic role of HLA-B27. One such hypothesis is that HLA-B27 can be recognized by CD4(+) T lymphocytes. Here we report the identification of such unusual cells, which break the conventional rules of MHC restriction, and propose a model for the role of such CD4(+) T cells in SpA.