The T Cell Repertoires from Nickel Sensitized Joint Implant Failure Patients

Abstract

Nickel (Ni2+) is one of the most common allergens, affecting around 10–15% of the general population. As the demand for orthopedic implant surgery rises, the number of surgical revisions due to joint implant failure also increases. There is evidence that some patients develop joint failure due to an immune response to a component of the implant, and we have found that Ni2+ is an especially important cause. Hence, understanding the mechanisms by which Ni2+ allergy induces joint implant failure becomes a critical research question. The structural basis of Ni2+ activation of pathogenic T cells is still not clear. The purpose of this study was to characterize Ni2+-reactive T cell repertoires derived from the peripheral blood of joint failure patients due to Ni2+ sensitization using single-cell sequencing techniques. We stimulated the proliferation of Ni2+ -reactive T cells from two implant failure patients in vitro, and sorted them for single-cell VDJ sequencing (10× genomics). We identified 2650 productive V-J spanning pairs. Both TCR α chains and β chains were enriched. TRBV18 usage is the highest in the P7 CD4+ population (18.1%), and TRBV5-1 usage is the highest in the P7 CD8+ population (12.1%). TRBV19 and TRBV20-1 segments are present in a high percentage of both P7 and P9 sequenced T cells. Remarkably, the alpha and beta chain combination of TRAV41-TRBV18 accounts for 13.5% of the CD4+ population of P7 patient. Compared to current Ni specific T cell repertoire studies of contact dermatitis, the Vα and Vβ usages of these joint implant failure patients were different. This could be due to the different availability of self-peptides in these two different tissues. However, TRBV19 (Vβ17) was among frequently used TCR β chains, which are common in previous reports. This implies that some pathogenic T cells could be similar in Ni2+ hypersensitivities in skin and joints. The alignment of the TCR CDR3β sequences showed a conserved glutamic acid (Glu) that could potentially interact with Ni2+. The study of these Ni2+ specific TCRs may shed light on the molecular mechanism of T cell activation by low molecular weight chemical haptens.

Immune response differences in degradable and non-degradable alloy implants

“…T cell mechanism of Ni-mediated hypersensitivity was studied in patients who have previously shown allergic reactions to Ni-containing CoCrMo. The result confirmed that a conserved glutamic acid in TCR CDR3β sequence provides a potential Ni binding site [ 122 ]. Although previous studies discussed the significant role of T cells in Ni-induced inflammation, a surprising study by Sato et al revealed that even nude mice (lacking mature T cells) have shown Ni allergy.…”

Unique and common TCR repertoire features of Ni2+‐, Co2+‐, and Pd2+‐specific human CD154 + CD4+ T cells

“…The increase of histidine‐containing CDR3 among metal‐specific TCR mirrored the histidine positions in the random repertoires, without indications for a preferred metal ion binding site. Apart from histidine, glutamic acid (E) has been discussed as a possible Ni 2+ ion binding site at the end of the CDR3β 56 . In our data, glutamic acid occurred frequently at position 4 (3′‐5′; 47% of random TCR; mean) but was not further increased among Ni 2+ ‐specific TCR (~42%; Figure S9).…”

“…Apart from histidine, glutamic acid (E) has been discussed as a possible Ni 2+ ion binding site at the end of the CDR3β. 56 In our data, glutamic acid occurred frequently at position 4 (3′-5′; 47% of random TCR; mean) but was not further increased among Ni 2+ -specific TCR (~42%; Figure S9).…”

“…However, other metal‐specific T cell clones strongly depend on a certain antigen‐presenting cell presenting distinct self‐peptides, which argues against a conventional superantigen‐like recognition 29,86 . Polar amino acids such as histidine, tyrosine, or glutamic acid have been discussed in Ni 2+ complexation 13,16,56 . Further crystallization and mutation studies are needed to identify the exact binding sites for which representative TCR may be selected considering the features identified in this study.…”

“…29,86 Polar amino acids such as histidine, tyrosine, or glutamic acid have been discussed in Ni 2+ complexation. 13,16,56 Further crystallization and mutation studies are needed to identify the exact binding sites for which representative TCR may be selected considering the features identified in this study.…”