DOMINANCE OF THE BV17 ELEMENT IN NICKEL-SPECIFIC HUMAN T-CELL RECEPTORS RELATES TO SEVERITY OF CONTACT SENSITIVITY

Hypersensitivity to nickel (Ni) represents the most common manifestati on of contact allergy in humans. The role of metal-specific T cells in this disease is well established, but the molecular interactions invo lved in their activation are poorly understood. We examined the T cell receptor (TCR) repertoire in T cells activated with either NiSO4 or N iSO4-treated human serum albumin from six allergic patients. For the t hree most hyperreactive donors, we found a strong over-represention of the TCR BV17 element. TCR sequencing for one of these donors revealed an additional skewing for AV1 as well as a selection for an N region encoded argine at position 95 of the BV17 complementarity determining region (CDR)3. Since Arg is not known to participate in Ni complexing, we suppose that this selection is driven by contacts with peptide rat her than nickel. However, the CDR1 of BV17 contains a unique combinati on of amino acids (HDA) that bears similarities to known motifs in Ni- binding proteins or peptides. We therefore propose that the severe hyp ersensitivity reactions found in BV17 over-expressors may be the resul t of Ni2+ ions bridging the germ-line- encoded BV17 CDR1 loop to corre sponding sites in the major histocompatibility complex/peptide complex and thereby creating a superantigen-like enhancement of weak TCR-pept ide contacts.