Allele-unrestricted presentation of lidocaine by HLA-DR molecules to specific alphabeta+ T cell clones

Abstract

T cells recognize peptide and non-peptide antigens. Drugs represent typical examples of non-peptide antigens. The majority of drug-specific T cells are alphabeta+ TCR T cells and are MHC class I or II restricted. Here we show the existence of drug (lidocaine)-specific T cell clones which proliferate in the presence of antigen-presenting cells (APC) with different HLA alleles. Two clones (SFT24 and E20) were analyzed in detail. They show a narrow dose-dependent proliferation to lidocaine, but not to procaine. With the use of a panel of HLA-typed allogeneic APC, we observed that certain allogeneic APC plus lidocaine lead to a similar, others to partial and some to no proliferation of the lidocaine-specific T cell clones. An APC-independent proliferation could be excluded since both clones proliferated only marginally without APC and increasing the number of APC resulted in a higher proliferation. Blocking experiments with anti-DP, -DQ and -DR antibodies showed that lidocaine is presented in a HLA-DR-restricted way both with autologous or allogeneic APC. Mouse fibroblasts transfected with an allogeneic HLA-DRB1*01 but not HLA-DR-negative mouse fibroblasts could serve as presenting cells. Fixation of APC did not hamper drug presentation, but pulsing of APC with the drug was not possible, indicating that processing is not required and that lidocaine binds in an unstable way to the MHC-peptide complex. This degenerate drug recognition has certain features of superantigen recognition, such as the ability of drugs to bind from the outside to multiple HLA-DR alleles. Such features of drug recognition may open new therapeutic possibilities to intervene with TCR-MHC interactions in a selective way.

Characterization of Drug-Specific T Cells in Phenobarbital- Induced Eruption

“…T cell recognition of antigenic moieties on APC is not so stringent as has been suggested, and promiscuous under certain settings. Allele-unrestricted presentation of haptenic small compounds by MHC class II molecules is recently described in the interactions between T cells specific for lidocaine, sulfamethoxazole, and amoxicillin and APC (16,27). Direct binding of nickel to particular amino acids of cryptic MHC peptides results in conformational change of the MHC-peptide-metal complex so as to be recognized by nickel-specific T cells irrespective of APC alleles (28).…”

“…It is suggested that "processing" or "covalent binding" of drug to MHC on APC is not necessary for T cell activation in sulfonamide and lidocaine hypersensitivities (10,16). Therefore, we examined requirement of processing by APC in phenobarbital hypersensitivity in clones A0 and A5 from patient A.…”

Characterization of Human T Cells That Regulate Neutrophilic Skin Inflammation

“…Drug-specific TCC isolated from peripheral blood of AGEP patients (patients AP and JS, amoxicillin; patient EB, celecoxib) and from skin biopsy specimens of positive epicutaneous patch tests (patients AP and JS) (Fig. 1B) were found to recognize the drug in an HLA-DR-, but not in an allele-restricted manner (data not shown) (21). Dose-response curves for three representative bloodderived CD4…”

Evolving models of the immunopathogenesis of T cell–mediated drug allergy: The role of host, pathogens, and drug response

“…37 Experiments demonstrating that some drugs are able to trigger T-cell responses in the absence of intracellular peptide processing, such as following the fixation of APCs, support this hypothesis. [38][39][40][41] This model has also been hypothesized to explain in vitro T-cell reactivity that has been observed within seconds of drug exposure, a time course that is inconsistent with intracellular antigen processing, or for IM-ADR that are observed following first encounter with a drug. 33,37 When IM-ADR adheres to the altered peptide repertoire model, the offending drug occupies a position in the peptide binding groove of the MHC protein thereby changing the chemistry of the binding cleft and the peptide specificity of MHC binding.…”