HLA-B27 (B27) is strongly associated with spondyloarthopathy. The classical role of B27 is to present peptides from intracellular pathogens as a heterotrimeric complex with beta2 microglobulin for recognition by the T-cell receptor (TCR) of CD8 T-cells. In addition to heterotrimers, B27 can also be expressed as cell surface beta2-microglobulin (beta2m)-free homodimers (B27(2)). In addition to the TCR, MHC class I molecules bind to immunoregulatory receptors including members of the killer immunoglobulin-like receptor (KIR) and leukocyte immunoglobulin-like receptor (LILR) families. Rodents express the paired immunoglobulin receptor (PIR) family which are related to LILR. B27(2) but not beta2m-associated B27 binds to KIR3DL2 and rodent PIR. NK and T-cells expressing the immune receptor KIR3DL2, which interacts with B27(2), are expanded in B27 AS patients. Ligation of immune receptors by B27(2) promotes the survival of KIR-expressing leukocytes and modulates immune cytokine production. Upregulation ofB272 in spondyloarthritis and differential interaction of beta2m-associated HLA-B27 and B27(2) with immune receptors could be involved in the pathogenesis of B27-associated spondyloarthritis (AS).