The MHC class I molecule, HLA-B27 can be expressed as a number of non-conventional forms, in addition to conventional HLA-B27 heterodimers presenting peptide. This has lead to new avenues of research to explain the association of this molecule with SpA. Surprisingly, HLA-B27 transgenic animal models implicated CD4+ T cells, which conventionally interact with MHC class II molecules, not MHC class I molecules, in the pathogenesis of SpA. One hypothesis to explain these finding is that non-conventional forms of HLA-B27, specifically HLA-B27 homodimers, might mimic MHC class II molecules and be recognised by CD4+ T cells. We investigated whether CD4+ T cells from AS patients can interact with HLA-B27, discovering that indeed CD4+ T cells can interact with various forms of HLA-B27. Here we discuss how such interactions between HLA-B27 and CD4+ T cells could occur in vivo and potential contributions of such interactions to the pathogenesis of SpA.