Engineering mouse T lymphocytes specific to type II collagen by transduction with a chimeric receptor consisting of a single chain Fv and TCR zeta

Abstract

The chimeric cell surface receptor scC2Fv/CD8/ was constructed to engineer primary mouse T lymphocytes with antibody-type specificity to type II collagen (CII). Such cells could be used as gene carriers in the anti-inflammatory gene therapy of an autoimmune arthritis. This receptor includes the single chain Fv domain (scFv) of the anti-CII monoclonal antibody (mAb) C2, hinge region of CD8␣ and the transmembrane and cytoplasmic domains of TCR. The scC2Fv/CD8/ gene was transduced into T cell hybridomas and primary mouse lymphocytes using retrovirus-mediated gene transfer. The chimeric receptor scC2Fv/CD8/ forms covalently bound homodimers, as demonstrated in T cell hybridomas and packaging fibroblasts. It does not associate

Gene therapy for arthritis

“…For these reasons, T cells have been engineered to recognize a joint antigen via a chimeric receptor comprised of an extracellular domain derived from an scFv of an anticollagen type II antibody fused to the signaling subunits of the g chain of the FceR1 67 or the CD3 z chain of the TCR. 68 These redirected T cells recognize unprocessed antigen in an MHC-independent fashion, secrete proinflammatory cytokines, and proliferate upon encounter with antigen. Upon transfer to naïve mice these cells can cause arthritis as do the Th1 arthritogenic T cells described above and can be recovered from lymph nodes up to three weeks …”

Fulminant experimental autoimmune encephalo-myelitis induced by retrovirally mediated TCR gene transfer

“…There has been increasing interest in the transfer of antigen specific T cells for antitumor therapy [28,30,32], or for boosting the immune system after ablation with chemotherapy to avoid reemergence of latent infections such as EBV [29]. Some groups have attempted to introduce chimeric TCR consisting of antibody V regions directly linked to TCR signaling molecules thus avoiding the need for appropriate MHC restriction for T cell activation [32,[35][36][37][38]. In developing such therapies, our system would provide an efficient method for testing multiple variants of a TCR for therapeutic effect.…”

CD8+ T Cells Induce Complete Regression of Advanced Ovarian Cancers by an Interleukin (IL)-2/IL-15–Dependent Mechanism

“…Although CD8 + T cells with similarly high avidity for tumor antigens are relatively rare in human cancer patients, they can be more readily isolated using tetramer technology (48). Moreover, advances in T-cell receptor engineering may ultimately bypass the need to identify and isolate naturally occurring T cells with such properties (49,50).…”