Dominance of the BV17 element in nickel‐specific human T cell receptors relates to severity of contact sensitivity

Abstract

Hypersensitivity to nickel (Ni) represents the most common manifestation of contact allergy in humans. The role of metal-specific T cells in this disease is well established, but the molecular interactions involved in their activation are poorly understood. We examined the T cell receptor (TCR) repertoire in T cells activated with either NiSO4 or NiSO4-treated human serum albumin from six allergic patients. For the three most hyperreactive donors, we found a strong over-representation 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 rather than nickel. However, the CDR1 of BV17 contains a unique combination of amino acids (HDA) that bears similarities to known motifs in Ni-binding proteins or peptides. We therefore propose that the severe hypersensitivity reactions found in BV17 over-expressors may be the result of Ni2+ ions bridging the germ-line-encoded BV17 CDR1 loop to corresponding sites in the major histocompatibility complex/peptide complex and thereby creating a superantigen-like enhancement of weak TCR-peptide contacts.

Metal-Protein Complex-Mediated Transport and Delivery of Ni2+ to TCR/MHC Contact Sites in Nickel-Specific Human T Cell Activation

“…Previous studies from our laboratory have already shown that human Ni-reactive T cell clones could indeed be induced by Ni 2ϩ complexed to HSA (HSA-Ni) (5,20). Subsequently, similar data have been reported by Artik et al (21) for murine T cells.…”

“…Human hypersensitivity to Ni, like contact allergies in animal models, is mediated by allergen-specific T cells (1,2,20). HLArestricted Ni-reactive T cell lines and clones of both CD4 and CD8 phenotypes have repeatedly been isolated by NiSO 4 or NiCl 2 stimulation of T cells from peripheral blood or skin lesions of allergic patients and even from nonsensitized individuals (1,9,44,45).…”

T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

“…In previous studies, we and others have shown that the human Tcell clone ANi2.3, isolated from a patient with nickel hypersensitivity, reacts with Ni ++ presented by the human MHCII protein DR52c bearing an unknown peptide (17,18). Our efforts to find this peptide among the peptides naturally processed and bound to DR52c failed, suggesting that it may be present in very low abundance.…”

Use of soluble peptide–DR4 tetramers to detect synovial T cells specific for cartilage antigens in patients with rheumatoid arthritis

“…These primers also included restriction sites to permit insertion of the amplified fragments into a TCR ␤-chain expression vector, pHBAcPrMC␤2, adjacent to murine C␤2 or a TCR ␣-chain expression vector, pSFFMC␣, adjacent to murine C␣ (E. Boen, A. Crownover, M. McIlhaney, A. Korman, and J.B., unpublished results). The chimeric TCR genes were introduced into the TCR-negative and human CD4-expressing T cell hybridoma 54 by electroporation as described (24). Transfectants were screened for surface expression of TCR and verified to be functional as determined by release of IL-2 after stimulation with an appropriate V␤-selective superantigen presented by autologous Epstein-Barr virus-transformed B cells.…”