Carrier‐reactive hapten‐specific cytotoxic T lymphocyte clones originate from a highly preselected T cell repertoire: implications for chemical‐induced self‐reactivity

Abstract

We have recently described trinitrophenyl (TNP)-specific cytotoxic T lymphocyte (CTL) clones from C57BL/6 mice specific for hapten-modified peptides bearing a TNP-lysine in a peripheral position, i.e. in position 7 of H-2Kb-bound octapeptides. CTL recognition of such determinants is always sequence-dependent due to co-recognition of TNP as well as amino acid side chains of the carrier peptide. By the use of glycine-based designer peptides for primary induction of CTL in vitro, we have identified two sub-epitopes on individual position 7-haptenated peptides that form two TcR contact points and which can be independently recognized by cloned CTL. One of these sub-epitopes is represented by the hapten itself, the other by the amino acids tyrosine and lysine in positions 3 and 4 of the carrier peptide, respectively. Immunization with such TNP-modified peptides frequently results in the specific induction of CTL also reacting with the unmodified carrier peptides. DNA sequence analyses of the TcR revealed an extraordinary similarity of several independent TcR of CTL from individual mice and induced with different TNP-peptides. These receptor similarities clearly correlate with structural elements common to the immunizing peptides and suggest their origin from positive thymic selection of TcR on Kb-associated associated self-peptides bearing Tyr in position 3. Our data provide additional information concerning the topology of TcR binding to peptide/MHC complexes with, but also without, TNP. They also indicate a mechanism which might explain the potential of chemicals or drugs to induce autoimmune phenomena.

A Novel Antibody-Based Biomarker for Chronic Algal Toxin Exposure and Sub-Acute Neurotoxicity

“…It is unlikely that DA alone would result in lymphocyte activation, but when coupled to carrier proteins in serum or on cells, it could modify self-proteins and thus act as a potent hapten for stimulating both B and T cell mediated responses including specific antibody production. Hapten modified self-proteins have been shown to elicit antibody production and T cell effector function [26], [27], [28], [29]. Specifically, a potential mechanism for DA mediated humoral responses observed in this study could include DA modification of self through reactive carbonyl groups on DA as shown for other small haptens [30].…”

Hapten-Induced Contact Hypersensitivity, Autoimmune Reactions, and Tumor Regression: Plausibility of Mediating Antitumor Immunity

“…Much of the justification for the work done was based on Weltzien's group's papers between 1992 and 1997, as earlier described [63, 64, 107, 108]. In this work, they saw the ability of hapten-specific CD8+ T-cell clones to recognize and respond to hapten bound and unbound portions of small tryptic fragments of proteins suggesting some cross-reactivity of the cells.…”

“…They showed that trinitrobenzene sulfonic acid (TNBS)-like haptens are H-2K b restricted [64]; haptenated Ag can be processed intracellular in the ER/Golgi to be presented by MHC I [63], and trinitrophenyl (TNP)-specific T-cell clones were able to recognize haptenated and unhaptenated portions of designed tryptic fragments of TNP-octapeptides [107]. TNP-specific CD4+ T-cell clones were able to recognize many different TNP-modified peptides, as long as TNP was present [108].…”

“…By injection of haptenated-BSA, BSA-tolerized rabbits were able to induce the production of antibody towards the hapten, the BSA, and the conjugate. Haptens have been shown to induce hapten-specific CD8+ T-cell cross-recognition of haptenated and unhaptenated octapeptides as previously described [107]. Kang et al [132] showed hapten-mediated autoimmunity experimentally in hen egg lysozyme (HEL)-transgenic (Tg) C57BL/6 (B6) mice that were immunized with HEL or hapten-modified (phosphorylcholine [PC]) HEL (PC-HEL).…”

Immunoproteomics

“…Moreover, there are numerous examples of atypical ligands possessing non-motif-based sequences, post-translationally modified ligands, or of the failure of antigen processing to liberate the candidate peptides that restrict predictive algorithms to a subset of T cell epitopes (67)(68)(69)(70)(71)(72)(73)(74)(75)(76). Furthermore, many T cell responses are focused on one or two immunodominant peptides selected from the numerous potential MHC-ligands encoded within the pathogen genome (77).…”